acetaminophen

National Center for Biotechnology Information. PubChem Compound Database; CID=1983, https://pubchem.ncbi.nlm.nih.gov/compound/1983 (accessed Feb. 19, 2017).
PubChem CID: 1983
Chemical Names: Acetaminophen; 4-Acetamidophenol; Paracetamol; 103-90-2; APAP; Tylenol   More...
Molecular Formula: C8H9NO2 or HOC6H4NHCOCH3
Molecular Weight: 151.165 g/mol
InChI Key: RZVAJINKPMORJF-UHFFFAOYSA-N
Drug Information:Drug Indication  Therapeutic Uses  Clinical Trials  FDA Orange Book  FDA UNII
Safety Summary: Laboratory Chemical Safety Summary (LCSS)
Analgesic antipyretic derivative of acetanilide. Acetaminophen has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage.
Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-mediated effects on the heat-regulating center in the anterior hypothalamus.
Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations.
Modify Date: 2017-02-12; Create Date: 2004-09-16

  1. 2D Structure
  2. 3D Conformer
  3. Names and Identifiers
    1. Computed Descriptors
      1. IUPAC Name
      2. InChI
      3. InChI Key
      4. Canonical SMILES
    2. Molecular Formula
    3. Other Identifiers
      1. CAS
      2. EC Number
      3. ICSC Number
      4. RTECS Number
      5. UNII
    4. Synonyms
      1. MeSH Synonyms
      2. Depositor-Supplied Synonyms
  4. Chemical and Physical Properties
    1. Computed Properties
    2. Experimental Properties
      1. Physical Description
      2. Color
      3. Odor
      4. Taste
      5. Boiling Point
      6. Melting Point
      7. Solubility
      8. Density
      9. Vapor Density
      10. Vapor Pressure
      11. LogP
      12. LogS
      13. Stability
      14. Auto-Ignition
      15. pH
      16. pKa
      17. Dissociation Constants
      18. Kovats Retention Index
    3. Crystal Structures
    4. Spectral Properties
      1. GC-MS
      2. MS-MS
      3. EI-MS
      4. 1D NMR
      5. 2D NMR
  5. Related Records
    1. Related Compounds with Annotation
    2. Related Compounds
    3. Substances
      1. Related Substances
      2. Substances by Category
    4. Entrez Crosslinks
  6. Chemical Vendors
  7. Drug and Medication Information
    1. Drug Indication
    2. LiverTox Summary
    3. Drug Classes
    4. FDA Orange Book
      1. Prescription Drug Products
      2. Over-the-Counter Drug Products
      3. Discontinued Drug Products
    5. Drug Labels for Ingredients
    6. Drugs at PubMed Health
    7. Clinical Trials
    8. Therapeutic Uses
    9. Drug Warning
    10. Minimum/Potential Fatal Human Dose
    11. Drug Tolerance
  8. Agrochemical Information
    1. Agrochemical Category
  9. Pharmacology and Biochemistry
    1. Pharmacology
    2. MeSH Pharmacological Classification
    3. ATC Code
    4. Absorption, Distribution and Excretion
    5. Metabolism/Metabolites
    6. Biological Half-Life
    7. Mechanism of Action
    8. Human Metabolite Information
      1. Metabolite Description
      2. Biofluid Locations
      3. Tissue Locations
      4. Cellular Locations
      5. Metabolite Pathways
  10. Use and Manufacturing
    1. Uses
      1. Consumer Uses
    2. Methods of Manufacturing
    3. Formulations/Preparations
    4. Consumption
    5. U.S. Production
    6. U.S. Imports
  11. Identification
    1. Analytic Laboratory Methods
    2. Clinical Laboratory Methods
    3. OSHA Chemical Sampling
  12. Safety and Hazards
    1. Hazards Identification
      1. GHS Classification
      2. Health Hazard
      3. Fire Hazard
      4. Fire Potential
    2. Safety and Hazard Properties
      1. Explosive Limits and Potential
    3. First Aid Measures
      1. First Aid
      2. Inhalation First Aid
      3. Skin First Aid
      4. Eye First Aid
      5. Ingestion First Aid
    4. Fire Fighting Measures
      1. Fire Fighting
    5. Accidental Release Measures
      1. Spillage Disposal
      2. Cleanup Methods
      3. Disposal Methods
      4. Other Preventative Measures
    6. Handling and Storage
      1. Nonfire Spill Response
      2. Safe Storage
      3. Storage Conditions
    7. Exposure Control and Personal Protection
      1. Occupational Exposure Limits
      2. Inhalation Risk
      3. Effects of Long Term Exposure
      4. Fire Prevention
      5. Exposure Prevention
      6. Inhalation Prevention
      7. Skin Prevention
      8. Eye Prevention
      9. Ingestion Prevention
      10. Protective Equipment and Clothing
    8. Stability and Reactivity
      1. Air and Water Reactions
      2. Reactive Group
      3. Reactivity Profile
      4. Reactivities and Incompatibilities
    9. Regulatory Information
      1. FDA Requirements
    10. Other Safety Information
      1. Toxic Combustion Products
  13. Toxicity
    1. Toxicological Information
      1. Heptatoxicity
      2. Carcinogen
      3. Exposure Routes
      4. Inhalation Symptoms
      5. Eye Symptoms
      6. Interactions
      7. Toxicity Summary
      8. Antidote and Emergency Treatment
      9. Human Toxicity Excerpts
      10. Non-Human Toxicity Excerpts
      11. Human Toxicity Values
      12. Non-Human Toxicity Values
      13. Ecotoxicity Values
      14. National Toxicology Program Reports
      15. Populations at Special Risk
      16. Protein Binding
    2. Ecological Information
      1. EPA Ecotoxicity
      2. ICSC Environmental Data
      3. Environmental Fate/Exposure Summary
      4. Artificial Sources
      5. Environmental Fate
      6. Biodegredation
      7. Abiotic Degredation
      8. Bioconcentration
      9. Soil Adsorption/Mobility
      10. Volatilization from Water/Soil
      11. Water Concentrations
      12. Effluents Concentrations
      13. Milk Concentrations
      14. Probable Routes of Human Exposure
  14. Literature
    1. Depositor Provided PubMed Citations
    2. NLM Curated PubMed Citations
    3. Synthesis References
    4. General References
    5. Metabolite References
  15. Patents
    1. Depositor-Supplied Patent Identifiers
    2. FDA Orange Book Patents
  16. Biomolecular Interactions and Pathways
    1. Protein Bound 3-D Structures
    2. Biosystems and Pathways
    3. DrugBank Interactions
  17. Biological Test Results
    1. BioAssay Results
  18. Classification
    1. Ontologies
      1. MeSH Tree
      2. ChEBI Ontology
      3. KEGG: Carcinogen
      4. KEGG: Drug
      5. KEGG: ATC
      6. KEGG: CYP
      7. KEGG: JP15
      8. KEGG: Risk Category of Japanese OTC Drugs
      9. KEGG: OTC drugs
      10. KEGG: Animal Drugs
      11. WHO ATC Classification System
      12. WIPO IPC
  19. Information Sources

  1. 2D Structure

    acetaminophen.png

  2. 3D Conformer

    • 8
    • 8
    • 7
    • 6
    • 6
    • 6
    • 6
    • 6
    • 6
    • 6
    • 6
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    • 1
    • 1
    • 1
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    • 1
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    • 1
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  3. Names and Identifiers

    1. Computed Descriptors

      1. IUPAC Name

        N-(4-hydroxyphenyl)acetamide

      2. InChI

        InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)

      3. InChI Key

        RZVAJINKPMORJF-UHFFFAOYSA-N

      4. Canonical SMILES

        CC(=O)NC1=CC=C(C=C1)O

    2. Molecular Formula

      C8H9NO2
      HOC6H4NHCOCH3

    3. Other Identifiers

      1. CAS

        103-90-2

      2. EC Number

        203-157-5

      3. ICSC Number

        1330

      4. RTECS Number

        AE4200000

      5. UNII

        362O9ITL9D

    4. Synonyms

      1. MeSH Synonyms

        1. Acamol
        2. Acephen
        3. Acetaco
        4. Acetamidophenol
        5. Acetaminophen
        6. Acetominophen
        7. Algotropyl
        8. Anacin 3
        9. Anacin-3
        10. Anacin3
        1. APAP
        2. Datril
        3. Hydroxyacetanilide
        4. N-(4-Hydroxyphenyl)acetanilide
        5. N-Acetyl-p-aminophenol
        6. p-Acetamidophenol
        7. p-Hydroxyacetanilide
        8. Panadol
        9. Paracetamol
        10. Tylenol

      2. Depositor-Supplied Synonyms

  4. Chemical and Physical Properties

    1. Computed Properties

      Properties computed automatically from the given chemical structure

      Molecular Weight:

      Molecular weight or molecular mass refers to the mass of a molecule. It is calculated as the sum of the mass of each constituent atom multiplied by the number of atoms of that element in the molecular formula.

      XLogP3:

      Computed Octanol/Water Partition Coefficient

      Hydrogen Bond Donor Count:

      Hydrogen Bond Donor count

      Hydrogen Bond Acceptor Count:

      Hydrogen Bond Acceptor count

      Rotatable Bond Count:

      Rotatable bond is defined as any single non-ring bond, bounded to nonterminal heavy (i.e., non-hydrogen) atom.

      Exact Mass:

      The exact mass of an isotopic species is obtained by summing the masses of the individual isotopes of the molecule.

      Monoisotopic Mass:

      The monoisotopic mass is the sum of the masses of the atoms in a molecule using the unbound, ground-state, rest mass of the principal (most abundant) isotope for each element instead of the isotopic average mass.

      Topological Polar Surface Area:

      The topological polar surface area (TPSA) of a molecule is defined as the surface sum over all polar atoms in a molecule.

      Heavy Atom Count:

      A heavy atom is defined as any atom except hydrogen in a chemical structure.

      Formal Charge:

      Formal charge is the difference between the number of valence electrons of each atom and the number of electrons the atom is associated with. Formal charge assumes any shared electrons are equally shared between the two bonded atoms.

      Complexity:

      The complexity rating of a compound is a rough estimate of how complicated a structure is, seen from both the point of view of the elements contained and the displayed structural features including symmetry. This complexity rating is computed using the Bertz/Hendrickson/Ihlenfeldt formula. Read more...

      Isotope Atom Count:

      Isotopte Atom Count is the number of isotopes that are not most abundant for the corresponding chemical elements. Isotopes are variants of a chemical element which differ in neutron number. For example, among three isotopes of carbon (i.e., C-12, C-13, and C-14), the isotope atom count considers the C-13 and C-14 atoms, because C-12 is the most abundant isotope of carbon.

      Defined Atom Stereocenter Count:

      An atom stereocenter, also known as a chiral center, is an atom that is attached to four different types of atoms (or groups of atoms) in the tetrahedral arrangement. It can have either (R)- or (S)- configurations. Some compounds, such as racemic mixtures, have an undefined atom stereocenter, whose (R/S)-configuration is not specifically defined.

      Undefined Atom Stereocenter Count:

      An atom stereocenter, also known as a chiral center, is an atom that is attached to four different types of atoms (or groups of atoms) in the tetrahedral arrangement. It can have either (R)- or (S)- configurations. Some compounds, such as racemic mixtures, have an undefined atom stereocenter, whose (R/S)-configuration is not specifically defined.

      Defined Bond Stereocenter Count:

      A bond stereocenter is a non-rotatable bond around which two atoms can have different arrangement (as in cis- and trans-forms of butene around its double bond). Some compounds have an undefined bond stereocenter, whose stereochemistry is not specifically defined.

      Undefined Bond Stereocenter Count:

      A bond stereocenter is a non-rotatable bond around which two atoms can have different arrangement (as in cis- and trans-forms of butene around its double bond). Some compounds have an undefined bond stereocenter, whose stereochemistry is not specifically defined.

      Covalently-Bonded Unit Count:

      Covalently-Bonded Unit Count

      Molecular Weight151.165 g/mol
      XLogP30.5
      Hydrogen Bond Donor Count2
      Hydrogen Bond Acceptor Count2
      Rotatable Bond Count1
      Exact Mass151.063 g/mol
      Monoisotopic Mass151.063 g/mol
      Topological Polar Surface Area49.3 A^2
      Heavy Atom Count11
      Formal Charge0
      Complexity139
      Isotope Atom Count0
      Defined Atom Stereocenter Count0
      Undefined Atom Stereocenter Count0
      Defined Bond Stereocenter Count0
      Undefined Bond Stereocenter Count0
      Covalently-Bonded Unit Count1

    2. Experimental Properties

      1. Physical Description

        COLOURLESS CRYSTALS OR CRYSTALLINE POWDER.
        Liquid, OtherSolid
        PHYSICAL DESCRIPTION: Odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6. (NTP, 1992)
        Solid

      2. Color

        Large monoclinic prisms from water
        O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10

      3. Odor

        Odorless
        Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

      4. Taste

        Slightly bitter taste
        Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

      5. Boiling Point

        >500°C

      6. Melting Point

        168 deg C
        Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-314
        169-171
        Merck Index 39
        169-170°C
        336 to 342° F (NTP, 1992)
        170 °C

      7. Solubility

        In water, 14,000 mg/L at 25 deg C
        Yalkowsky, S.H., He, Yan, Jain, P. Handbook of Aqueous Solubility Data Second Edition. CRC Press, Boca Raton, FL 2010, p. 492
        Very slightly soluble in cold water, soluble in boiling water
        O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
        Freely soluble in alcohol; soluble in methanol, ethanol, dimethylformamide, ethylene dichloride, acetone, ethyl acetate; slightly soluble in ether; practically insoluble in petroleum ether, pentane, benzene
        O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
        Water Solubility
        14000 mg/L (at 25 °C)
        YALKOWSKY,SH & DANNENFELSER,RM (1992)
        in water, g/100ml at 20°C: 1.4 (moderate)
        >22.7 [ug/mL]
        1 to 5 mg/mL at 72° F (NTP, 1992)
        14 mg/mL at 25 °C

      8. Density

        1.293 g/cu cm at 21 deg C
        Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 94th Edition. CRC Press LLC, Boca Raton: FL 2013-2014, p. 3-314
        1.3 g/cm³
        1.293 at 70° F (NTP, 1992)

      9. Vapor Density

        (air = 1): 5.2

      10. Vapor Pressure

        6.29X10-5 mm Hg at 25 deg C
        Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989.

      11. LogP

        log Kow = 0.46
        Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html
        0.46
        SANGSTER (1994)
        0.49

      12. LogS

        -1.03
        ADME Research, USCD

      13. Stability

        Stable under recommended storage conditions.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

      14. Auto-Ignition

        540°C

      15. pH

        Saturated aqueous solution: 5.5-6.5
        Lewis, R.J. Sr.; Hawley's Condensed Chemical Dictionary 15th Edition. John Wiley & Sons, Inc. New York, NY 2007., p. 11

      16. pKa

        9.38
        DASTMALCHI,S ET AL. (1995)

      17. Dissociation Constants

        pKa = 9.38
        Dastmalchi S et al; J Sch Pharm, Med Sci Univ Tehran 4: 7-14 (1995)

      18. Kovats Retention Index

        Standard non-polar1668, 1636, 1631, 1631, 1632, 1643, 1650, 1664, 1678, 1675.7, 1694.6, 1652.3, 1631, 1636, 1687
        Semi-standard non-polar1694, 1697, 1703, 1693.1

    3. Crystal Structures

      Crystal Structures: 1 of 31
      CCDC Number129925
      Crystal Structure DataDOI:10.5517/cc4c64t
      Associated ArticleDOI:10.1107/S0108270197018386
      Crystal Structures: 2 of 31
      CCDC Number135451
      Crystal Structure DataDOI:10.5517/cc4jydz
      Associated ArticleDOI:10.1021/js970483d
      Crystal Structures: 3 of 31
      CCDC Number135452
      Crystal Structure DataDOI:10.5517/cc4jyf0
      Associated ArticleDOI:10.1021/js970483d
      View All 31 Crystal Structures

    4. Spectral Properties

      UV max (ethanol): 250 nm (epsilon 13800)
      O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10
      Intense mass spectral peaks: 80 m/z, 109 m/z, 151 m/z
      Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 206
      MASS: 4765 (NIST/EPA/MSDC Mass Spectral database, 1990 version)
      Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 58
      IR: 5420 (Coblentz Society spectral collection)
      Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 58
      UV: 2913 (Sadtler Research Laboratories spectral collection)
      Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 58
      Raman: 930 (Sadtler Research Laboratories spectral collection)
      Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 58

      1. GC-MS

        GC-MS Spectrum
        1 of 6
        NIST Number229798
        LibraryMain library
        Total Peaks69
        m/z Top Peak109
        m/z 2nd Highest151
        m/z 3rd Highest43
        Thumbnail

      2. MS-MS

        1. MS-MS Spectrum
        2. MS-MS Spectrum
        3. MS-MS Spectrum
        4. MS-MS Spectrum
        5. MS-MS Spectrum
        6. MS-MS Spectrum
        1 of 3
        NIST Number1000869
        Instrument TypeIT/ion trap
        Spectrum TypeMS2
        Precursor Type[M+H]+
        Precursor m/z152.0706
        Total Peaks5
        m/z Top Peak110
        m/z 2nd Highest152
        m/z 3rd Highest111
        Thumbnail

      3. EI-MS

        EI-MS Spectrum

      4. 1D NMR

        1. 1D NMR - 1H NMR Spectrum
        2. 1D NMR - 1H NMR Spectrum
        3. 1D NMR - 13C NMR Spectrum

      5. 2D NMR

        2D NMR - 1H-13C NMR Spectrum

  5. Chemical Vendors

    Vendor/SupplierPurchasable ChemicalPubChem SID
    Sigma-AldrichA3035_SIAL24890717
    A5000_SIAL24890930
    A7085_SIAL24891173
    A7302_ALDRICH24891200
    CAPOT17726152239051
    PubChem17726143489358
    Life ChemicalsF3096-1731252091812
    Boc Sciences103-90-2254759318
    AKos Consulting & SolutionsAKOS000121004104669427
    Ark Pharm, Inc.AK-42438163374224
    SyntreeST24028862249848694
    Chembase.cn105412162092342
    201160963664
    1717 CheMall CorporationBT000165253676311
    OR040311254078386
    OR275224254212019
    OR343575254279576
    OR354404254290101
    Angene ChemicalAGN-PC-006QMP172456000
    Vitas-M LaboratoryBBL005229125321456
    STL140694124999640
    MolepediaM90003113P252404216
    King ScientificKSC492K1N163808951
    CambridgeChemB112079318354465
    abcr GmbHAB113247316393966
    Alsachim1261198991323
    BioChemPartnerBCP0726000305136946686
    BCP9000225144115533
    BCPP000441136368135
    ChemSceneCS-2819210276581
    WutechRP21489174552589
    Yuhao ChemicalRT12770318242163
    AbovChem LLCHY-66005319553271
    TractusRTR-000905204394950
    TR-000905204935981
    TRA0127672252272712
    Green Chempharm Inc50-4930250177519
    Chem-Space.com DatabaseCSC000184395318304745
    eNovation ChemicalsD516853319476452
    Parchem11769316962385
    37981316971888
    BePharm Ltd.B112079275889420
    ChemMol1202927126589960
    44001940126657118
    49417442126678793
    98000234135699159
    99163344241154240
    Nanjing KaimuboKB-188932172842043
    KB-192758172844971
    KB-74449172918096
    Oakwood Products005037117648674
    AcadechemACDS-017269321906287
    A&J Pharmtech CO., LTD.AJ-70539223579710
    CJ-15887223501241
    TargetMolT0065312693371
    T0065-10mg313363225
    T0065-20mg318483181
    T0065-25mg313365856
    T0065-5mg312698419
    AN PharmaTechAN-24662223653262
    Finetech Industry LimitedFT-0658035164831811
    ChemTikCTK3J2516162760834
    AchemicaACMC-20989w162283189
    AnwardANW-14994160782495
    AK Scientific, Inc. (AKSCI)H865162177616
    Key Organics/BIONETSTR00901249742040
    MP Biomedicals19009185083200
    21138551071779
    IS Chemical TechnologyI05-008681040782
    Race ChemicalRV022508493252219863
    ACT ChemicalACT06727172440074
    BiocoreBIE062976312627659
    TCI (Tokyo Chemical Industry)H019087570622
    ZINCZINC13550868259325137
    ZINC1827477760813397
    MedChemexpress MCEHY-66005210281428
    Wolves R&D chemicalEBD5728223367416
    AmbinterBB_SC-7122102852099
    SelleckchemAcetaminophen125164196
    Acetaminophen-Supplied by Selleck Chemicals124757392
    S1634_Selleck104253270
    BoerchemBC204766196111431
    AHH Chemical co.,ltdMT-46428252344499
    Glentham Life Sciences Ltd.GK4314310265363
    Aurora Fine Chemicals LLCA00.157.692292370289
    OXCHEM CORPORATIONAX8112079255400850
    MculeMCULE-3844920617169518868
    TimTecSBB043758143422391
    ST45179777144022619
    ClearsynthCS-O-30999313077347
    ABBLIS ChemicalsAB1009347125311792
    iChemicalEBD5728318021737
    ChemDiv0099-0228328084631
    NORRIS PHARMTH-D05802312284631
    Hangzhou APIChem TechnologyAC-23969316903505
    ChemFrog888-885-550125336940
    Tocris Bioscience1706252156051
    Bide Pharmatech Ltd.BD112079252033564
    Founder PharmaFD10326250194851

  6. Drug and Medication Information

    1. Drug Indication

      For temporary relief of fever, minor aches, and pains.

    2. LiverTox Summary

      Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations.

    3. Drug Classes

      Nonsteroidal Antiinflammatory Drugs

    4. FDA Orange Book

      1. Prescription Drug Products

        Prescription Drug Products: 1 of 28
        Drug IngredientACETAMINOPHEN
        Proprietary NameACETAMINOPHEN
        Applicant
        1. FRESENIUS KABI USA (Application Number: N204767)
        2. PADDOCK LLC (Application Number: A202605)
        3. SANDOZ INC (Application Number: A204052)
        Prescription Drug Products: 2 of 28
        Drug IngredientACETAMINOPHEN
        Proprietary NameOFIRMEV
        ApplicantMALLINCKRODT IP (Application Number: N022450. Patents: 6028222, 6028222*PED, 6992218, 6992218*PED, 9399012, 9399012*PED)
        Prescription Drug Products: 3 of 28
        Drug IngredientACETAMINOPHEN; BUTALBITAL
        Proprietary NameALLZITAL
        ApplicantLARKEN LABS INC (Application Number: A203484)
        View All 28 Prescription Drug Products

      2. Over-the-Counter Drug Products

        Over-the-Counter Drug Products: 1 of 7
        Drug IngredientACETAMINOPHEN
        Proprietary NameACEPHEN
        Applicant
        1. G AND W LABS (Application Number: A072237)
        2. G AND W LABS (Application Number: A072344)
        3. G AND W LABS (Application Number: N018060)
        Over-the-Counter Drug Products: 2 of 7
        Drug IngredientACETAMINOPHEN
        Proprietary NameACETAMINOPHEN
        Applicant
        1. AUROBINDO PHARMA LTD (Application Number: A207229)
        2. OHM LABS (Application Number: A076200)
        3. PERRIGO NEW YORK (Application Number: A070607)
        4. PERRIGO NEW YORK (Application Number: A070608)
        5. PERRIGO (Application Number: A075077)
        6. SUN PHARM INDS LTD (Application Number: A078569)
        7. TARO PHARMS NORTH (Application Number: N018337)
        Over-the-Counter Drug Products: 3 of 7
        Drug IngredientACETAMINOPHEN
        Proprietary NameINFANTS' FEVERALL
        ApplicantTARO PHARMS NORTH (Application Number: N018337)
        View All 7 Over-the-Counter Drug Products

      3. Discontinued Drug Products

        Discontinued Drug Products: 1 of 88
        Drug IngredientACETAMINOPHEN
        Proprietary NameACEPHEN
        ApplicantG AND W LABS (Application Number: A072218)
        Discontinued Drug Products: 2 of 88
        Drug IngredientACETAMINOPHEN
        Proprietary NameINJECTAPAP
        ApplicantORTHO MCNEIL PHARM (Application Number: N017785)
        Discontinued Drug Products: 3 of 88
        Drug IngredientACETAMINOPHEN
        Proprietary NameTYLENOL
        ApplicantJ AND J CONSUMER INC (Application Number: N017756)
        View All 88 Discontinued Drug Products

    5. Drug Labels for Ingredients

      Label InformationTotal 4874 labels
      Drug IngredientACETAMINOPHEN
      NDC Code(s)
      NDC Code(s)
      0023-0419-01, 0023-0420-01, 0023-0420-05, 0023-0430-01, 0023-0430-05, 0023-0431-01, 0023-0431-05, 0023-6002-01, 0023-6021-01, 0023-6021-05 ... total 9732.
      PackagersLlorens Pharmaceutical International Division; 7-Eleven; A P J Laboratories Limited; A&Z Holistic Products, Inc.; A-S Medication Solutions; A-S Medication Solutions LLC; AAA Pharmaceutical, Inc.; AAFES/Your Military Exchanges; ACTIPHARMA, INC; ADVANCED FIRST AID, INC. ... total 597.

    6. Drugs at PubMed Health

      Drugs at PubMed Health: 1 of 12
      Drug NameAcetaminophen
      Drug ClassesAnalgesic, Antipyretic
      Drugs at PubMed Health: 2 of 12
      Drug NameAcetaminophen (By injection)
      DescriptionRelieves pain and reduces fever.
      Drug ClassesAnalgesic
      Drugs at PubMed Health: 3 of 12
      Drug NameAcetaminophen (By mouth)
      DescriptionTreats minor aches and pain and reduces fever.
      Drug ClassesAnalgesic, Antipyretic
      View All 12 Drugs at PubMed Health

    7. Clinical Trials

      1 to 5 of 609
      View More
      Record IDTitleStatusPhase
      NCT02785549Multicentre Controlled, Randomized Clinical Trial to Compare the Efficacy and Safety of Ambulatory Treatment of Mild Acute Diverticulitis Without Antibiotics With the Standard Treatment With AntibioticsRecruiting4
      NCT01235949Impact of Immediate or Delayed Prophylactic Antipyretic Treatment on the Immunogenicity, Reactogenicity and Safety of GlaxoSmithKline Biologicals' Pneumococcal Vaccine 1024850A and the Co-administered DTPa-combined VaccinesCompleted4
      NCT03011905Rebound Pain at Block Resolution After Operations for Distal Radius Fractures With a Volar Plate in Brachial Plexus BlockNot yet recruiting3
      NCT03012763Pharmacokinetics of Sulfasalazine, Paracetamol, Fexofenadine and Valsartan After Oral Administration Using 240 ml Non-caloric Water, a Carbohydrate Enriched Drink and Grapefruit Juice in Correlation to the Intestinal Availability of Water as Quantified by MRI-based Volumetry in 9 Healthy Male and Female SubjectsCompleted1
      NCT02061774Postoperative Opioid Use and Pain Scores in Patients Undergoing Transforaminal Lumbar Interbody Fusion After Administration of Preoperative Followed by Scheduled Intravenous Acetaminophen:Recruiting4

    8. Therapeutic Uses

      Analgesics, Non-Narcotic; Antipyretics
      National Library of Medicine's Medical Subject Headings. Acetaminophen. Online file (MeSH, 2014). Available from, as of January 30, 2014: http://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html
      Ofirmev (acetaminophen) injection is indicated for the management of mild to moderate pain the management of moderate to severe pain with adjunctive opioid analgesics the reduction of fever. /Included in US product label/
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      Acetaminophen is used to provide temporary analgesia in the treatment of mild to moderate pain. Acetaminophen also is used in fixed combination with other agents (e.g., chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) for short-term relief of minor aches and pain, headache, and/or other symptoms (e.g., rhinorrhea, sneezing, lacrimation, itching eyes, oronasopharyngeal itching, nasal congestion, cough) associated with seasonal allergic rhinitis (e.g., hay fever), other upper respiratory allergies, or the common cold.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      Acetaminophen has been used in the treatment of pain in various combinations with aspirin, caffeine, opiates, and/or other agents. Acetaminophen ... in combination with oral doses of an opiate (e.g., codeine, oxycodone) produces greater analgesic effect than that produced by either acetaminophen or higher doses of the opiate alone.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      Acetaminophen in fixed combination with aspirin and caffeine ... is used for the temporary relief of mild to moderate pain associated with migraine headache. Some experts state that this combination also may be used for the treatment of severe migraine headache if previous attacks have responded to similar nonopiate analgesics or nonsteroidal anti-inflammatory agents (NSAIAs).
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      Acetaminophen in fixed combination with isometheptene and dichloralphenazone also is used for symptomatic relief of vascular headaches.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      Acetaminophen is used in the symptomatic treatment of pain associated with osteoarthritis and is considered an initial drug of choice for pain management in osteoarthritis patients.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      If an antipyretic is considered necessary in children or teenagers with known or suspected varicella, influenza-like illness, or other viral illness, use of acetaminophen (not aspirin) is recommended because use of salicylates in these pediatric patients may be associated with an increased risk of developing Reye's syndrome.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2207
      Acetaminophen is used frequently to lower body temperature in febrile patients in whom fever may be deleterious or in whom considerable relief is obtained when fever is lowered.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      Acetaminophen in fixed combination with isometheptene and dichloralphenazone is used for symptomatic relief of tension headache.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2206
      MEDICATION (VET): In arthritic & inflammatory syndromes to relieve pain & reduce fever.
      Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974., p. 1

    9. Drug Warning

      The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal. Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. ... Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers. Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.
      US FDA; FDA Drug Safety Communication: FDA Warns of Rare but Serious Skin Reactions with the Pain Reliever/Fever Reducer Acetaminophen (8/1/2013). Available from, as of March 6, 2014: http://www.fda.gov/drugs/drugsafety/ucm363041.htm
      FDA is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of acetaminophen1 per tablet, capsule, or other dosage unit. There are no available data to show that taking more than 325 mg of acetaminophen per dosage unit provides additional benefit that outweighs the added risks for liver injury. Further, limiting the amount of acetaminophen per dosage unit will reduce the risk of severe liver injury from inadvertent acetaminophen overdose, which can lead to liver failure, liver transplant, and death.
      US FDA; FDA Drug Safety and Availability: FDA recommends health care professionals discontinue prescribing and dispensing prescription combination drug products with more than 325 mg of acetaminophen to protect consumers (1/14/2014). Available from, as of March 9, 2014: http://www.fda.gov/Drugs/DrugSafety/ucm381644.htm
      /BOXED WARNING/ WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY. Take care when prescribing, preparing, and administering Ofirmev Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (mL) is not confused; the dosing is based on weight for patients under 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits. Ofirmev contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophen-containing product.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance = 30 mL/min).
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      When acetaminophen is used in fixed combination with other agents (e.g., antihistamines, aspirin, caffeine, dextromethorphan, dichloralphenazone, guaifenesin, isometheptene, nasal decongestants, opiate agonists), the usual cautions, precautions, and contraindications associated with these agents must be considered in addition to those associated with acetaminophen.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Acetaminophen is relatively nontoxic in therapeutic doses when taken as directed. However, acetaminophen overdosage has been the leading cause of acute liver failure (with encephalopathy and coagulopathy) in the US, United Kingdom, and most of Europe, with about 50% of US cases in recent years resulting from inadvertent overdosage (e.g., in patients not recognizing the presence of the drug in multiple over-the-counter (OTC) and/or prescription products that they may be taking). Therefore, patients should be warned about the importance of determining whether acetaminophen is present in their medications (e.g., by examining labels carefully, by consulting their clinician and pharmacist) and of not exceeding recommended dosages or combining acetaminophen-containing preparations. Many OTC drug products and prescription preparations contain acetaminophen. In fact, acetaminophen, alone or in combination, is one of the most commonly used drugs in the US. Simultaneous use of more than one preparation containing acetaminophen can result in adverse consequences (e.g., acetaminophen overdose). Patients should be advised not to take multiple acetaminophen-containing preparations concomitantly.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Dermatologic reactions including pruritic maculopapular rash and urticaria have been reported and other sensitivity reactions including laryngeal edema, angioedema, and anaphylactoid reactions may occur rarely.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Thrombocytopenia, leukopenia, and pancytopenia have been associated with the use of p-aminophenol derivatives, especially with prolonged administration of large doses. Neutropenia and thrombocytopenic purpura have been reported with acetaminophen use. Rarely, agranulocytosis has been reported in patients receiving acetaminophen.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. There were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. Discontinue Ofirmev immediately if symptoms associated with allergy or hypersensitivity occur. Do not use Ofirmev in patients with acetaminophen allergy.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      Some commercially available formulations of acetaminophen contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals. Acetaminophen should be discontinued if hypersensitivity reactions occur.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Skin rash & other allergic reactions occur occasionally. Rash is usually erythematous or urticarial but sometimes it is more serious & may be accompanied by drug fever & mucosal lesions.
      Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 704
      Because concomitant administration of acetaminophen (especially when administered in high dosages or for prolonged periods) with oral anticoagulants may potentiate the effects of the oral anticoagulant, additional monitoring of prothrombin time (PT)/international normalized ratio (INR) values has been suggested for patients receiving oral anticoagulants following initiation of, or during sustained therapy with, large doses of acetaminophen.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Because chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol. The manufacturers currently caution that patients who generally consume 3 or more alcohol-containing drinks per day should ask their clinician whether to use acetaminophen or an alternative analgesic for self-medication. However, FDA has proposed eliminating this statement from the labeling of OTC acetaminophen-containing preparations and adding a new warning that would highlight the potential for severe liver damage to occur in individuals who consume 3 or more alcohol-containing drinks per day while taking acetaminophen, in those who use more than one acetaminophen-containing product concomitantly, and in those who exceed the recommended daily dosage of the drug.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration (i.e., with therapeutic intent), parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. Parents also should be cautioned not to use other acetaminophen-containing products (e.g., some cold and cough products) concomitantly with acetaminophen in children because of the potential for overdoses.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Parents and caregivers should be advised about the appropriate dose, frequency, duration of therapy, and specific strength and formulation for an individual pediatric patient. They also should be advised of the danger of substituting alternative dosage forms, particularly adult for pediatric formulations. Parents and caregivers should be warned not to exceed recommended acetaminophen dosages and cautioned that children should not be allowed to administer the drug themselves. They also should be warned to read the labeled contents of over-the-counter (OTC) preparations, particularly those recommended for cold, cough, fever, headache, and general ache and pain because simultaneous use of more than one preparation containing acetaminophen could be dangerous. In addition, they should be warned not to substitute extended-release formulations for immediate-release (conventional) ones without making appropriate changes in the dosing interval.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Severe liver dysfunction occurred in 2 individuals who took 3.6 g/day acetaminophen for symptoms of infectious mononucleosis. All lab variables returned to normal following acetaminophen withdrawal.
      Rosenberg D, Neelon F; Ann Intern Med 88 (JAN): 129 (1978)
      Paracetamol should be given with care to patients with impaired kidney or liver function. ... Paracetamol should be given with care to patients taking other drugs that affect the liver.
      Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 269
      Individuals with phenylketonuria (ie, homozygous deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that Children's Tylenol and Junior Strength Tylenol chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine following oral administration.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208
      Acetaminophen is contraindicated: in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation and in patients with severe hepatic impairment or severe active liver disease.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d
      Of the total number of subjects in clinical studies of Ofirmev, 15% were age 65 and over, while 5% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      While studies with Ofirmev have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 - 2% of the maternal dose. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Caution should be exercised when Ofirmev is administered to a nursing woman.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-day period. Rapid identification of the symptoms of SJS and TEN caused by ingestion of acetaminophen enabled prompt withdrawal of the culprit drug. After administration of intravenous immunoglobulin G, both patients recovered fully and were discharged. These two cases of rapidly developed SJS/TEN after ingestion of acetaminophen highlight the possibility that these complications can develop within only a few days following ingestion of over-the-counter medications such as acetaminophen.[Kim EJ et al; Asia Pac Allergy 4 (1): 68-72 (2014)] Full text: PMC3921868 Abstract: PubMed

    10. Minimum/Potential Fatal Human Dose

      In adults, hepatic toxicity rarely has occurred with acute overdoses of less than 10 g, although hepatotoxicity has been reported in fasting patients ingesting 4-10 g of acetaminophen. Fatalities are rare with less than 15 g.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2210

    11. Drug Tolerance

      Although psychologic dependence on acetaminophen may occur, tolerance and physical dependence do not appear to develop even with prolonged use.
      Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 2181

  7. Agrochemical Information

    1. Agrochemical Category

      Special Use

  8. Pharmacology and Biochemistry

    1. Pharmacology

      Acetaminophen (USAN) or Paracetamol (INN) is a widely used analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is extremely safe in standard doses, but because of its wide availability, deliberate or accidental overdoses are not uncommon. Acetaminophen, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties or effects on platelet function, and it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. At therapeutic doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, kidney function, or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics, acetaminophen does not cause euphoria or alter mood in any way. Acetaminophen and NSAIDs have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal. Acetaminophen is used on its own or in combination with pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, doxylamine, codeine, hydrocodone, or oxycodone.
      Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-mediated effects on the heat-regulating center in the anterior hypothalamus.

    2. MeSH Pharmacological Classification

      Antipyretics
      Drugs that are used to reduce body temperature in fever. See a list of PubChem compounds matching this category.
      Analgesics, Non-Narcotic
      A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS. See a list of PubChem compounds matching this category.

    3. ATC Code

      N02BE01 - Paracetamol < N02BE - Anilides < N02B - Other analgesics and antipyretics < N02 - Analgesics < N - Nervous system

    4. Absorption, Distribution and Excretion

      Acetaminophen is rapidly and almost completely absorbed from the GI tract following oral administration. In healthy men, steady-state oral bioavailability of 1.3-g doses of extended-release tablets of acetaminophen administered every 8 hours for a total of 7 doses was equal to 1-g doses of conventional tablets of acetaminophen given every 6 hours for a total of 7 doses. Food may delay slightly absorption of extended-release tablets of acetaminophen. Following oral administration of immediate- or extended-release acetaminophen preparations, peak plasma concentrations are attained within 10-60 or 60-120 minutes, respectively. Following oral administration of a single 500-mg conventional tablet or a single 650-mg extended-release tablet, average plasma acetaminophen concentrations of 2.1 or 1.8 ug/mL, respectively, occur at 6 or 8 hours, respectively. In addition, dissolution of the extended-release tablets may depend slightly on the gastric or intestinal pH. Dissolution appears to be slightly faster in the alkaline pH of the intestines compared with the acidic pH of the stomach; however, this is of no clinical importance. Following administration of conventional preparations of acetaminophen, only small amounts of the drug are detectable in plasma after 8 hours. The extended-release tablets of acetaminophen release the drug for up to 8 hours, but in vitro data indicate that at least 95% of the dose is released within 5 hours.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      Following rectal administration of acetaminophen, there is considerable variation in peak plasma concentrations attained, and time to reach peak plasma concentrations is substantially longer than after oral administration.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      In 12 nursing mothers (nursing 2-22 months) given a single oral dose of 650 mg, peak levels of acetaminophen occurred at 1-2 hours in the range of 10-15 ug/mL. Assuming 90 mL of milk were ingested at 3-, 6-, and 9-hour intervals after ingestion, the amount of drug available to the infant was estimated to range from 0.04% to 0.23% of the maternal dose.
      Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 11
      Acetaminophen is rapidly and uniformly distributed into most body tissues. About 25% of acetaminophen in blood is bound to plasma proteins.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      Acetaminophen is excreted in urine principally as acetaminophen glucuronide with small amounts of acetaminophen sulfate and mercaptate and unchanged drug. Approximately 85% of a dose of acetaminophen is excreted in urine as free and conjugated acetaminophen within 24 hours after ingestion. Administration of acetaminophen to patients with moderate to severe renal impairment may result in accumulation of acetaminophen conjugates.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      /Acetaminophen/ crosses the placenta.
      Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 2
      High carbohydrate meals reduced GI absorption rates ... in humans. Possible mechanism may be reaction of drug with pectin, present in some carbohydrate meals. As acetaminophen is absorbed from stomach as well as small intestine, changes in gastric emptying should not greatly alter absorption rate.
      The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 419
      The elimination rate and plasma clearance of paracetamol are both significantly reduced in individuals aged 65 years or over.
      The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979., p. 25
      Acetaminophen (APAP) is a popular analgesic. In the present study, /the authors/ characterized the pharmacokinetics and pharmacodynamics of APAP in the Japanese. Five healthy volunteers were administered 1000 mg of APAP orally. Five patients with chronic pain were administered the optimal oral dose of APAP ranging from 600 to 1000 mg to allow for an adequate analgesic effect. Plasma APAP and APAP metabolite concentrations were measured in the volunteers, plasma APAP concentrations and pain scores using a visual analog scale were measured in the patients with chronic pain. Patient data were fitted to a first-order absorption one-compartment model with delayed effects accounted for by an effect compartment. A sigmoid Emax model was used as the pharmacodynamic model. Acetaminophen-cysteine metabolites, which are conjugates of the toxic metabolite N-acetyl-p-benzoquinone-imine, were detected in the plasma at levels lower than 0.2 ug/mL, but no side effects were observed. The pharmacokinetic and pharmacodynamic parameter (mean+/-S.D.) estimates were as follows: clearance, 18.7+/-4.7 L/hr; distribution volume, 30.9+/-6.8 L; absorption rate constant, 2.4+/-1.3 hr(-1); rate constant for the elimination of APAP from the effect compartment, 1.3+/-0.5 hr(-1); maximum pain relief score, 4.6+/-2.2 units; effect compartment concentration at 50% maximum, 2.0+/-1.2 ug/mL; and sigmoid factor, 1.3+/-0.7. These results suggest that these parameters can be used to determine an effective APAP dosage regimen for Japanese patients with chronic pain. Abstract: PubMed
      Shinoda S et al; Biol Pharm Bull 30 (1): 157-61 (2007)
      After oral administration paracetamol is rapidly and almost completely absorbed in humans and animal species. virtually no absorption occurs from the stomach. Absorption from the small intestine is rapid ... Distribution is rapid and uniform. The compound is weakly lipid soluble and appears in most body fluids. The apparent volume of distribution is about 1 L/kg. Plasma binding is low in humans at therapeutic levels, increasing at higher doses. bioavailability in humans ranges from 68% at a dose of 0.5 g to 90% at a dose of 1.2 g. In dogs, an oral dose of paracetamol was reported to be distributed in almost all organs, except fat. Highest tissue levels were found in liver and kidneys.
      European Medicines Agency (EMA), Committee for Veterinary Medicinal Products: Paracetamol; Summary Report (EMEA/MRL/551/99-FINAL) p.1 (February 1999). Available from, as of March 9, 2014: http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500015516.pdf
      The content of acetaminophen in the blood, tissues and body fluid was measured at autopsy of a 25-yr-old female who died from a suicidal overdose of imipramine, acetominophen, codeine diphenhydramine, and ethanol. (Empty bottles of Novopramine 50 mg (imipramine) and Tylenol #1 (acetaminophen 300 mg, codeine 8 mg, caffeine 15 mg) were found; the quantity of alcohol imbibed was not known). Blood samples were taken from at least 10 arterial and venous sites, and other samples were taken from 24 tissues, cerebrospinal fluid, vitreous humor and bile. Acetominophen showed a narrow concentration range (55-65 mg/L) in postmortem blood, but high concentrations were found in the kidney (187 mg/kg in right renal cortex and 148 mg/kg in left renal medulla). Abstract: PubMed
      Jones GR, Pounder DJ; J Anal Toxicol 11 (5): 186-90 (1987)
      Rapid and almost complete
      Route of Elimination
      Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted unchanged.

    5. Metabolism/Metabolites

      About 80-85% of the acetaminophen in the body undergoes conjugation principally with glucuronic acid and to a lesser extent with sulfuric acid. Acetaminophen also is metabolized by microsomal enzyme systems in the liver.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis and that high doses of acetaminophen may deplete glutathione so that inactivation of this toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternative pathways. In addition, it also has been suggested that in fasting individuals conjugation of high doses of acetaminophen with glucuronic acid may be reduced, secondary to decreased hepatic carbohydrate reserves and microsomal oxidation may be increased, resulting in increased risk of hepatotoxicity.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      Yields 4-acetamidocatechol in rat; yields s-(5-acetamido-2-hydroxyphenyl)-l-cysteine probably in man. Yields p-acetamidophenyl-beta-d-glucuronide in rabbit; yields p-acetamidophenyl-beta-d-glucuronide in rat, in guinea pig, & in ferret; yields p-acetamidophenyl-beta-d-glucuronide in man & in dog; yields p-acetamidophenyl sulfate in rabbit, guinea pig, & ferret; yields p-acetamidophenyl sulfate in rat & in man; yields p-methoxyacetanilide in guinea pig; yields quinol probably in rat. /From table/
      Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. A-10
      Children have less capacity for glucuronidation of the drug than do adults. A small proportion of acetaminophen undgoes n-hydroxylation to form n-acetyl-benzoquinoneimine, a highly reactive intermediate. This metabolite normally reacts with sulfhydryl groups in glutathione. However, after large doses of acetaminophen the metabolite is formed in amounts sufficient to deplete hepatic glutathione; under these circumstances reaction with sulfhydryl groups in hepatic proteins is increased and hepatic necrosis can result.
      Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 704
      The liver biotransforms 90% of accetaminophen by conversion in sulfate or glucuronide. The sulfate pathway predominates in children under 12 years of age, whereas adults primarily use the glucuronide pathway. Unchanged renal excretion accounts for less than 5% of the elimination. A small portion of the therapeutic dose (about 5% with an upper limit of 15% to 20%) is metabolized by the p450 mixed-function oxidase pathway to a reactive intermediary. In the presence of adequate glutathione stores, this intermediary is detoxified to mercapturic acid conjugates and cysteine. Formation of oxidative metabolities and renal excretion appear to follow first-order kinetics (ie, elimination rate is concentration dependent); the conjugation of sulfate and glucuronide metabolites follow Michaelis-Menten kinetic (combined zero- and first-order).
      Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 157
      Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI). With therapeutic doses, NAPQI undergoes rapid conjugation with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm.[Ganetsky M et al; J Clin Pharmacol. 53 (4): 413-20 (2013)] Full text: PMC4383763 Abstract: PubMed
      Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut. 30-35% of the dose undergoes sulfation. This biotransformation is facilitated by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is oxidized by CYP2E1 to form N-acetyl-p-benzo-quinone imine (NAPQI), a toxic metabolite which is then conjugated to glutathione and excreted renally. Studies suggest that CYP3A4 and CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated.

    6. Biological Half-Life

      The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose.
      OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
      1 to 4 hours

    7. Mechanism of Action

      Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
      The effects of acetaminophen on cyclooxygenase activity have not been fully determined. Acetaminophen is a weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. The inhibitory effect of acetaminophen on cyclooxygenase-1 is limited, and the drug does not inhibit platelet function. Therapeutic doses of acetaminophen appear to have little effect on cardiovascular and respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
      Acetaminophen (N-acetyl-p-aminophenol (APAP)) is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, /the researchers/ hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use. Abstract: PubMed
      Nassini R et al; FASEB J 24 (12): 4904-16 (2010)
      Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with acetaminophen intoxication. A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically. The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher (p < 0.001). Results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments. Abstract: PubMed
      Karadas S et al; Hum Exp Toxicol 33 (11): 1134-40 (2014)
      The mechanism by which acetaminophen (APAP) causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD) compared to male C57BL/6 mice in order to identify the cause(s) of sensitivity. Furthermore, /the researchers/ use mice that are either heterozygous (HZ) or null (KO) for glutamate cysteine ligase modifier subunit (Gclm), in order to titrate the toxicity relative to wild-type (WT) mice. Gclm is important for efficient de novo synthesis of glutathione (GSH). APAP (300 mg/kg, ip) or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 hr. Male mice showed marked elevation in serum alanine aminotransferase by 6 hr. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP-protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.[Mohar I et al; Redox Biol 2: 377-87 (2014)] Full text: PMC3926121 Abstract: PubMed
      One of the products of normal metabolism of acetaminophen by cytochrome p450 mixed-function oxidase enzymes is highly toxic; normally this reactive metabolite (NAPQI) is detoxified rapidly by glutathione in liver cells. however, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver injury.
      OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
      Acetaminophen (APAP) overdose causes liver injury in humans and mice. DNA fragmentation is a hallmark of APAP-induced cell death, and nuclear translocation of apoptosis-inducing factor (AIF) correlates with DNA fragmentation after APAP overdose. To test the hypothesis that AIF may be a critical mediator of APAP-induced cell death, fasted male AIF-deficient Harlequin (Hq) mice and respective wild-type (WT) animals were treated with 200 mg/kg APAP. At 6 h after APAP, WT animals developed severe liver injury as indicated by the increase in plasma alanine aminotransferase (ALT) activities (8600 + or - 1870 U/l) and 61 + or - 8% necrosis. This injury was accompanied by massive DNA strand breaks in centrilobular hepatocytes (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay) and release of DNA fragments into the cytosol (anti-histone ELISA). In addition, there was formation of reactive oxygen (increase in liver glutathione disulfide (GSSG) levels and mitochondrial protein carbonyls) and peroxynitrite (nitrotyrosine (NT) staining) together with mitochondrial translocation of activated c-jun-N-terminal kinase (P-JNK) and release of AIF from the mitochondria. In contrast, Hq mice had significantly less liver injury (ALT: 330 + or - 130 U/l; necrosis: 4 + or - 2%), minimal nuclear DNA damage, and drastically reduced oxidant stress (based on all parameters) at 6 h. WT and Hq mice had the same baseline levels of cyp2E1 and of glutathione. The initial depletion of glutathione (20 min after APAP) was the same in both groups suggesting that there was no relevant difference in metabolic activation of APAP. Thus, AIF has a critical function in APAP hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation.[Bajt ML et al; Toxicol Sci 122 (2): 598-605 (2011)] Full text: PMC3155087 Abstract: PubMed
      Acetaminophen (APAP) overdose is the leading cause of acute liver failure in Western countries. In the last four decades much progress has been made in our understanding of APAP-induced liver injury through rodent studies. However, some differences exist in the time course of injury between rodents and humans. To study the mechanism of APAP hepatotoxicity in humans, a human-relevant in vitro system is needed. Here we present evidence that the cell line HepaRG is a useful human model for the study of APAP-induced liver injury. Exposure of HepaRG cells to APAP at several concentrations resulted in glutathione depletion, APAP-protein adduct formation, mitochondrial oxidant stress and peroxynitrite formation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase (LDH) release. Importantly, the time course of LDH release resembled the increase in plasma aminotransferase activity seen in humans following APAP overdose. Based on propidium iodide uptake and cell morphology, the majority of the injury occurred within clusters of hepatocyte-like cells. The progression of injury in these cells involved mitochondrial reactive oxygen and reactive nitrogen formation. APAP did not increase caspase activity above untreated control values and a pancaspase inhibitor did not protect against APAP-induced cell injury. These data suggest that key mechanistic features of APAP-induced cell death are the same in human HepaRG cells, rodent in vivo models, and primary cultured mouse hepatocytes. Thus, HepaRG cells are a useful model to study mechanisms of APAP hepatotoxicity in humans.[McGill MR et al; Hepatology 53 (3): 974-82 (2011)] Full text: PMC3073317 Abstract: PubMed
      Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870 + or - 180U/L) and centrilobular necrosis at 6h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. ... The impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis.[Ramachandran A et al; Toxicol Appl Pharmacol 251 (3): 226-33 (2011)] Full text: PMC3050115 Abstract: PubMed
      Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. The antipyretic properties of acetaminophen are likely due to direct effects on the heat-regulating centres of the hypothalamus resulting in peripheral vasodilation, sweating and hence heat dissipation.

    8. Human Metabolite Information

      1. Metabolite Description

        The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. (PMID: 15733027). Single doses of paracetamol are effective analgesics for acute postoperative pain and give rise to few adverse effects. (PMID: 14974073). Acetaminophen (AAP) overdose and the resulting hepatotoxicity is an important clinical problem. In addition, AAP is widely used as a prototype hepatotoxin to study mechanisms of chemical-induced cell injury and to test the hepatoprotective potential of new drugs and herbal medicines. Because of its importance, the mechanisms of AAP-induced liver cell injury have been extensively investigated and controversially discussed for many years. (PMID: 16863451).

      2. Biofluid Locations

        1. Blood
        2. Cerebrospinal Fluid (CSF)
        3. Saliva
        4. Urine

      3. Tissue Locations

        All Tissues

      4. Cellular Locations

        Cytoplasm

      5. Metabolite Pathways

        1. Acetaminophen Action Pathway
        2. Acetaminophen Metabolism Pathway

  9. Use and Manufacturing

    1. Uses

      1. Consumer Uses

        Personal Care Products

    2. Methods of Manufacturing

      p-Nitrophenol is reduced and the resulting p-aminophenol is acetylated by means of heating with a mixture of acetic anhydride and glacial acetic acid. The crude product may be purified by recrystallization from an ethanol-water mixture.
      Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1541
      Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80 deg C, with acetic anhydride in pyridine at 100 deg C, with acetyl chloride and pyridine in toluene at 60 deg C, or by the action of ketene in alcoholic suspension. 4-Hydroxyacetanilide also may be synthesized directly from 4-nitrophenol. The available reduction-acetylation systems include tin with acetic acid, hydrogenation over Pd-C in acetic anhydride, and hydrogenation over platinum in acetic acid.
      Mitchell SC, Waring RH; Aminophenols. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2014). NY, NY: John Wiley & Sons. Online Posting Date: September 15, 2000
      Preparation: ... Wilbert, De Angelis, United States of America patent 2998450 (1961 to Warner-Lambert).
      O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 10

    3. Formulations/Preparations

      Acetaminophen Preparations

      Route of Administration Dosage Form Strength Brand or Generic Name (Manufacturer)
      Oral Capsules 500 mg Acetaminophen Capsules (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Solution 167 mg/5 mL Tylenol Extra-Strength Adult (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Solution 100 mg/mL Tylenol Concentrated Drops Infant's (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Suspension 160 mg/5 mL Tylenol Oral Suspension Chilcren's (McNeil)
      Oral Suspension 160 mg/5 mL Tylenol Oral Suspension Infant's (McNeil)
      Oral Tablets 325 mg Tylenol Regular Strength, scored (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Tablets 500 mg Tylenol Extra-Strength Rapid Release Gelcaps (McNeil) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Tablets, extended-release, film coated 650 mg Tylenol Arthritis Pain Extended Relief Caplets (McNeil)
      Oral Tablets, film-coated 500 mg Anacin Aspirin Free Extra Strength caplets (Insight) Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Oral Tablets, film-coated 500 mg Tylenol Extra Strength Caplets (McNeil)
      Oral Tablets, orally disintegrating 80 mg Tylenol Meltaways Children's (McNeil)
      Oral Tablets, orally disintegrating 160 mg Tylenol Meltaways Junior Strength (McNeil)
      Rectal Suppositories 80 mg FeverAll Infants' (Alpharma)
      Rectal Suppositories 120 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Rectal Suppositories 120 mg FeverAll Children's (Alpharma)
      Rectal Suppositories 125 mg Acetaminophen Suppositories Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Rectal Suppositories 325 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      Rectal Suppositories 325 mg FeverAll Junior Strength (Alpharma)
      Rectal Suppositories 650 mg Acephen (G&W) (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
      American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212
      Ofirmev: (acetaminophen) injection: 1000 mg/100mL (10 mg/mL)
      US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
      Common combination products containing acetaminophen include the following: Darvocet, Excedrin ES, Lorcet, Norco, NyQuil, Percocet, Unisom dual relief formula, Sominex 2, tylenol with Codeine, Tylenol PM, Tylox, Vicks formula 44-D, and Vicodin.
      OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
      Proprietary Preparation: Crocin (India)
      SWEETMAN, S.C. (ed.) Martindale-The Complete Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 111

    4. Consumption

      PRINCIPALLY USED AS A MEDICINAL (1976).
      SRI
      Acetaminophen. Analgesic, 75%; exports, 25%.
      Kavaler AR; Chemical Marketing Reporter 234 (25): 50 (1988)
      CHEMICAL PROFILE: Acetaminophen. Demand: 1987: 30 million lb; 1988: 30.5 million lb; 1992 /projected/: 31.5 million lb (Includes exports, but not imports, which totaled about 5 million lb last year.)
      Kavaler AR; Chemical Marketing Reporter 234 (25): 50 (1988)

    5. U.S. Production

      (1975) 4.5X10+9 GRAMS (INCL PHENACETIN)
      SRI
      (1976) GREATER THAN 2.27X10+6 GRAMS
      SRI
      Acetaminophen was one of the most used pharmaceuticals in England during 2002, at an amount used per year of 390,954.26 kg and has been detected in the environment.
      Jones OAH et al; Water Res 36: 1202-11 (2002)
      Production volumes for non-confidential chemicals reported under the Inventory Update Rule.
      Year Production Range (pounds)
      1986 10 thousand - 500 thousand
      1990 No Reports
      1994 >500 thousand - 1 million
      1998 10 thousand - 500 thousand
      2002 No Reports
      US EPA; Non-confidential Production Volume Information Submitted by Companies for Chemicals Under the 1986-2002 Inventory Update Rule (IUR). Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of March 6, 2014: http://epa.gov/cdr/tools/data/2002-vol.html
      Production volume for non-confidential chemicals reported under the 2006 Inventory Update Rule. Chemical: Acetamide, N-(4-hydroxyphenyl)-. Aggregated National Production Volume: < 500,000 pounds.
      US EPA; Non-Confidential 2006 Inventory Update Reporting. National Chemical Information. Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of March 6, 2014: http://cfpub.epa.gov/iursearch/index.cfm
      Non-confidential 2012 Chemical Data Reporting (CDR) information on the production and use of chemicals manufactured or imported into the United States. Chemical: Acetamide, N-(4-hydroxyphenyl)-. National Production Volume: 1,768,884 lb/yr.
      USEPA/Pollution Prevention and Toxics; 2012 Chemical Data Reporting Database. Acetamide, N-(4-hydroxyphenyl)- (103-90-2). Available from, as of March 6, 2014: http://java.epa.gov/oppt_chemical_search/

    6. U.S. Imports

      (1972) 9.1X10+7 GRAMS (PRINCPL CUSTMS DISTS)
      SRI
      (1975) 3.46X10+8 GRAMS (PRINCPL CUSTMS DISTS)
      SRI

  10. Identification

    1. Analytic Laboratory Methods

      High performance liquid chromatography analysis of acetaminophen with UV detector. Flow rate is 215 mL/min, wavelength is 254 nm fixed or 250 nm variable.
      Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975., p. 104
      Acetaminophen is determined by reverse phase liquid chromatography using methanol-acetic acid mobile phase and ultraviolet detection at 280 nm in single component drug tablets and in multi-component tablets containing aspirin and caffeine.
      Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990, p. 554 VI 987.12
      Analyte: acetaminophen; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
      Analyte: acetaminophen; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
      Analyte: acetaminophen; matrix: chemical identification; procedure: thin-layer chromatography with comparison to standards
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
      Analyte: acetaminophen; matrix: chemical purity; procedure: ultraviolet absorption spectrophotometry at 244 nm with comparison to standards
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1266 (2007)
      Analyte: acetaminophen; matrix: pharmaceutical preparation (capsule; effervescent oral solution; extended-release tablet; oral solution; suppository; tablet); procedure: retention time of the major peak of the liquid chromatogram with comparison to standards (chemical identification)
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1267 (2007)
      Analyte: acetaminophen; matrix: pharmaceutical preparation (capsule; effervescent oral solution; oral solution; suppository; tablet); procedure: thin-layer chromatography with comparison to standards (chemical identification)
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1267 (2007)
      Analyte: acetaminophen; matrix: pharmaceutical preparation (capsule; effervescent oral solution; oral solution; oral suspension; suppository; tablet); procedure: liquid chromatography with detection at 243 nm and comparison to standards (chemical purity)
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1267 (2007)
      Analyte: acetaminophen; matrix: pharmaceutical preparation (extended-release tablet; oral suspension); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1269 (2007)
      Analyte: acetaminophen; matrix: pharmaceutical preparation (extended-release tablet); procedure: liquid chromatography with detection at 295 nm and comparison to standards (chemical purity)
      U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1270 (2007)

    2. Clinical Laboratory Methods

      An acetaminophen test system is a device intended to measure acetaminophen, an analgestic and fever reducing drug, in serum. Measurements obtained by this device are used in the diagnosis and treatment of acetaminophen overdose.
      21 CFR 862.3030 (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 4, 2014: http://www.ecfr.gov/cgi-bin/ECFR?page=browse
      Urine, colorimetry; chromatography, gas-liquid.
      Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975., p. 13
      Samples used were from rat blood. HPLC method is sensitive enough to detect 0.05 mg/L of phenacetin & 0.25 mg/L of acetaminophen in presence of their metabolites in biological fluids. Abstract: PubMed
      Pang KS et al; J Chromatogr 174 (1): 165 (1979)
      Determination of phenacetin in blood plasma of animals by gas chromatography.
      Kyo Y, Niwa H; Tohoku Yakka Daigaku Kenkyu Nempo 25: 71 (1978)
      The amount of analgesic consumed and the time it was consumed is determined by urine analysis using either thin layer chromatography or colorimetry. Abstract: PubMed
      Kobbe K, goenechea S; Beitr Gerichtl Med 40: 341 (1982)
      High performance liquid chromatography (HPLC) methods were developed for the analysis of acetaminophen in postmortem blood. Abstract: PubMed
      Wong AS; J Anal Toxicol 7 (1): 33 (1983)
      A method for spectrometric measurement of acetaminophen at 615 nm is described which is rapid and precise enough for emergency lab use in blood analysis.
      Price CP et al; Clin Chem (Winston-Salem, NC) 29 (2): 358 (1983)
      A differential pulse voltammetric method was evaluated for determination of toxic levels of acetaminophen in in vitro human plasma samples. Abstract: PubMed
      Munson JW, abdine A; J Pharm Sci 67 (Dec): 1775 (1978)

    3. OSHA Chemical Sampling

      Tylenol

  11. Safety and Hazards

    1. Hazards Identification

      1. GHS Classification

        Signal: Warning
        GHS Hazard Statements
        Aggregated GHS information from 43 notifications provided by 251 companies to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

        H302 (98.8%): Harmful if swallowed [Warning Acute toxicity, oral - Category 4]
        H315 (25.5%): Causes skin irritation [Warning Skin corrosion/irritation - Category 2]
        H319 (25.1%): Causes serious eye irritation [Warning Serious eye damage/eye irritation - Category 2A]
        H335 (10.36%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation - Category 3]
        H412 (40.24%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard - Category 3]

        Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from all companies. Only Hazard Codes with percentage values above 10% are shown.

        Precautionary Statement Codes
        P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501
        (The corresponding statement to each P-code can be found here.)
        View GHS Classification from all (3) sources.

      2. Health Hazard

        SYMPTOMS: Symptoms of overexposure to this compound include nausea, vomiting, cyanosis from methemoglobinemia, injury to the liver, kidneys, central nervous system and heart, circulatory collapse, drowsiness, confusion, liver tenderness, low blood pressure, cardiac arrhythmias, jaundice, acute renal failure, death due to liver necrosis, metabolic acidosis, hepatic damage and cirrhosis. Other symptoms include changes in exocrine pancreas, diarrhea, irritability, somnolence, general anesthesia, fever and hepatitis. Diaphoresis and general malaise may occur. Exposure may lead to hematological reactions and, occasionally, skin rashes and other allergic reactions. The rash is usually erythematous or urticarial, but sometimes it is more serious and may be accompanied by drug fever and mucosal lesions. Exposure to large amounts may lead to pallor, anorexia, abdominal pain, abnormalities of glucose metabolism and hepatic encephalopathy. It may also lead to epigastric pain, sweating, paresthesias of distal extremities, muscular aching, weakness, dizziness, central nervous system depression (rare), pain in the upper right quadrant, enlarged liver, oliguria, anuria, coagulation defects and myocardiopathy characterized by ST segment abnormalities, T-wave flattening and pericarditis. This compound can cause purpura, generalized bleeding and hypoglycemia. It can also cause neutropenia, pancytopenia, leukopenia, thrombocytopenia and nephrotoxicity. Other symptoms may include wheezing, general discomfort, blood changes including many anemias (aplastic anemia), central nervous system stimulation, swollen tongue, rapid pulse, skin eruptions, chills, excitement, delirium, vascular collapse and convulsions. Irritation of the skin, eyes, mucous membranes and upper respiratory tract may occur. ACUTE/CHRONIC HAZARDS: This compound may be harmful by ingestion and inhalation. It may cause irritation of the skin, eyes, mucous membranes and upper respiratory tract. When heated to decomposition it emits toxic fumes of carbon monoxide, carbon dioxide and nitrogen oxides. (NTP, 1992)

      3. Fire Hazard

        Combustible.
        Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

      4. Fire Potential

        Not flammable or combustible.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

    2. Safety and Hazard Properties

      1. Explosive Limits and Potential

        vol% in air: 15 - ?

    3. First Aid Measures

      1. First Aid

        EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

      2. Inhalation First Aid

        Fresh air, rest.

      3. Skin First Aid

        Rinse and then wash skin with water and soap.

      4. Eye First Aid

        Rinse with plenty of water (remove contact lenses if easily possible).

      5. Ingestion First Aid

        Give one or two glasses of water to drink.

    4. Fire Fighting Measures

      Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special protective equipment for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.
      Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

      1. Fire Fighting

        Use powder, alcohol-resistant foam, water spray, carbon dioxide.
        Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

    5. Accidental Release Measures

      1. Spillage Disposal

        Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Sweep spilled substance into covered containers. If appropriate, moisten first to prevent dusting. Do NOT let this chemical enter the environment.

      2. Cleanup Methods

        Personal precautions: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

      3. Disposal Methods

        SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
        SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.
        Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

      4. Other Preventative Measures

        Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of the work day.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

    6. Handling and Storage

      1. Nonfire Spill Response

        SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this material from exposure to light. Keep it away from oxidizing materials and store it under ambient temperatures. (NTP, 1992)

      2. Safe Storage

        Provision to contain effluent from fire extinguishing. Store in an area without drain or sewer access.

      3. Storage Conditions

        Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: 00370, Version 3.6 (Revision Date 11/22/2012). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        Ofirmev should be stored at 20 deg C to 25 deg C (68 deg F to 77 deg F). ... Do not refrigerate or freeze.
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: ttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
        Acetaminophen preparations should be stored at a temperature less than 40 deg C, preferably between 15-30 deg C; freezing of the oral solution or suspension should be avoided.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2212

    7. Exposure Control and Personal Protection

      1. Occupational Exposure Limits

        TLV not established. MAK (not established):.

      2. Inhalation Risk

        A nuisance-causing concentration of airborne particles can be reached quickly.

      3. Effects of Long Term Exposure

        Ingestion may cause effects on the kidneys and liver. This may result in impaired functions.

      4. Fire Prevention

        NO open flames.

      5. Exposure Prevention

        PREVENT DISPERSION OF DUST!

      6. Inhalation Prevention

        Use local exhaust or breathing protection.

      7. Skin Prevention

        Protective gloves.

      8. Eye Prevention

        Wear safety goggles.

      9. Ingestion Prevention

        Do not eat, drink, or smoke during work.

      10. Protective Equipment and Clothing

        Hand protection: Handle with gloves.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        Skin and body protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html
        RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

    8. Stability and Reactivity

      1. Air and Water Reactions

        Slightly soluble in water.

      2. Reactive Group

        Amides and Imides
        Phenols and Cresols

      3. Reactivity Profile

        4-HYDROXYACETANILIDE is sensitive to light. Incompatible with strong oxidizers. (NTP, 1992).

      4. Reactivities and Incompatibilities

        Oxidizing agents
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

    9. Regulatory Information

      1. FDA Requirements

        The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
        DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 4, 2014: http://www.fda.gov/cder/ob/
        The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed over-the-counter drug products, including acetaminophen, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
        DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 4, 2014: http://www.fda.gov/cder/ob/

    10. Other Safety Information

      1. Toxic Combustion Products

        Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx).
        Sigma-Aldrich; Material Safety Data Sheet for Acetaminophen, Product Number: A5000, Version 4.4 (Revision Date 05/31/2013). Available from, as of March 7, 2014: http://www.sigmaaldrich.com/safety-center.html

  12. Toxicity

    1. Toxicological Information

      1. Heptatoxicity

        Chronic therapy with acetaminophen in doses of 4 grams daily has been found to lead to transient elevations in serum aminotransferase levels in a proportion of subjects, generally starting after 3 to 7 days, and with peak values rising above 3-fold elevated in 39% of persons. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage, and in some instances resolve even with continuation at full dose (Case 1).

      2. Carcinogen

        Evaluation: There is inadequate evidence in humans for the carcinogenicity of paracetamol. There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol. Overall evaluation: Paracetamol is not classifiable as to its carcinogenicity to humans (Group 3).
        IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php , p. 73 438 (1999)

      3. Exposure Routes

        The substance can be absorbed into the body by ingestion.

      4. Inhalation Symptoms

        Cough.

      5. Eye Symptoms

        Redness.

      6. Interactions

        Acetaminophen causes dose-dependent decrease in concentration of hepatic glutathione. Agents such as diethyl maleate, which depletes hepatic glutathione, potentiate /hepatic & renal tubular/ necrosis. Conversely, administration of cysteine, glutathione precursor, protects against damage.
        The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 544
        At certain dose levels ... pretreatment with phenobarbitone stimulated disappearance of paracetamol from tissues, but markedly potentiated hepatic necrosis. By contrast, pretreatment with piperonyl butoxide inhibited both metabolism and disappearance of paracetamol from tissues, and ... afforded protection against hepatic necrosis.
        The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 612
        Rate & extent of absorption of per oral dosed paracetamol is reduced by ... concomitant doses of caffeine, by propantheline & metoclopromide, & also by ... cholestyramine.
        The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 128
        A preliminary study in four subjects indicated that acetaminophen (3.0 g/day for 5 days) somewhat reduced the 96 hour urinary excretion of diazepam and its metabolites following a single 10 mg dose of diazepam. The effect was greater in the two female subjects, but additional study is needed to confirm these results and to define the magnitude of the interaction.
        Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985., p. 379
        Reports of the administration of 1.0 g of acetaminophen with food in four adult male volunteers demonstrated a considerable reduction in the rate of absorption of the drug with little change in the total amount of acetaminophen absorbed. The meal consisted of 200 mL orange juice, 30 g cornflakes, and Pop Tarts. In another study high carbohydrate test meals (crackers, jelly, and dates) significantly delayed absorption of acetaminophen as measured by urinary excretion. It was noted that high protein, high lipid, or balanced meals appeared to have little inhibitory effect on the rate of absorption.
        Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985., p. 380
        Because there is some evidence that chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        Anticonvulsants (including phenytoin, barbiturates, carbamazepine) that induce hepatic microsomal enzymes may increase acetaminophen-induced liver toxicity because of increased conversion of the drug to hepatotoxic metabolites. The risk of acetaminophen-induced hepatic toxicity is substantially increased in patients ingesting larger than recommended dosages of acetaminophen while receiving anticonvulsants. ... Patients should limit self-medication with acetaminophen while receiving anticonvulsants.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        Concomitant administration of isoniazid with acetaminophen may result in an increased risk of hepatotoxicity, but the exact mechanism of this interaction has not been established. The risk of hepatic toxicity is substantially increased in patients ingesting larger than recommended dosages of acetaminophen while receiving isoniazid. Therefore, patients should limit self-medication with acetaminophen while receiving isoniazid.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        Chronic ingestion of large doses of acetaminophen has been reported to potentiate the effects of coumarin- and indandione-derivative anticoagulants, although conflicting data exist and the clinical importance of any such interaction has been questioned. The results of an observational study in patients stabilized on warfarin therapy indicate an association between ingestion of even low to moderate dosages of acetaminophen (7 or more 325-mg tablets weekly) and excessively high international normalized ratio (INR) values, and some clinicians suggest that additional monitoring of INR values may be prudent in patients receiving warfarin therapy following initiation of, and during sustained therapy with, large doses of acetaminophen.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        The possibility of severe hypothermia should be considered in patients receiving concomitant phenothiazine and antipyretic (e.g., acetaminophen) therapy.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. /It was/ previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40mg/L) were treated by acetaminophen (APAP, 400mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p<0.01) and AST (p<0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p<0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination. Abstract: PubMed
        Gueguen Y et al; Toxicology 229 (1-2): 62-72 (2006)
        /The objective of this study was/ To determine whether concomitant administration of ciprofloxacin has any effect on the release and absorption of paracetamol. Ten healthy female volunteers received a single oral dose of paracetamol 1g or paracetamol 1g plus ciprofloxacin 500mg in a double-blind, crossover study. Pharmacokinetic parameters were measured in salivary samples using a colorimetric method. Maximum paracetamol concentration (C(max)) in saliva was significantly decreased when co-administered with ciprofloxacin (19.50 vs 13.70 microg/mL, p < 0.05). Time to paracetamol C(max) was significantly increased (1.43hr vs 0.77hr; p < 0.05) and paracetamol half-life was prolonged (1.19 to 1.53hr, p = 0.05) in the presence of ciprofloxacin, whereas the area under the concentration-time curve was not affected. Concomitant administration of ciprofloxacin with paracetamol may result in a delayed onset of action of paracetamol. Abstract: PubMed
        Issa M et al; Clin Drug Investig 26 (4): 223-6 (2006)
        Acetaminophen has been reported either to prolong or not to affect the clearance of chloramphenicol. To confirm one of these findings we studied the clearance of chloramphenicol and its metabolites using high pressure liquid chromatography in five patients (ages 2.5 to 5 years) before and during oral treatment with acetaminophen (50 mg/kg/day). Significant differences were observed in mean (SD) peak serum chloramphenicol concentration (-9.7 (3.2) mg/L), mean (SD) apparent volume of distribution (+225 (162) mL/kg), mean (SD) chloramphenicol half life (-1.9 (1.1) hours), mean (SD) chloramphenicol clearance (+236 (94) mL/kg/hr), mean (SD) area under the curve (-83.5 (33.0) mg/L/hr), and mean (SD) elimination constant (+0.34 (0.13) hr-1) between samples obtained before and during treatment with acetaminophen. Acetaminophen, when given orally for several days, increased the clearance of chloramphenicol, perhaps by increased glucuronidation. This report re-emphasises the need for therapeutic drug monitoring whenever these two drugs are used together.[Spika J et al; Arch Dis Child 61 (11): 1121-4 (1986)] Full text: PMC1778078 Abstract: PubMed
        Ozone (O(3)), an oxidant air pollutant in photochemical smog, principally targets epithelial cells lining the respiratory tract. However, changes in gene expression have also been reported in livers of O(3)-exposed mice. The principal aim of the present study was to determine if acute exposure to environmentally relevant concentrations of O(3) could cause exacerbation of drug-induced liver injury in mice. Overdose with acetaminophen (APAP) is the most common cause of drug-induced liver injury in developed countries. In the present study, ... the hepatic effects of acute O(3) exposure in mice pretreated with a hepatotoxic dose of APAP /was studied/. C57BL/6 male mice were fasted overnight and then given APAP (300 mg/kg ip) or saline vehicle (0 mg/kg APAP). Two hours later, mice were exposed to 0, 0.25, or 0.5 ppm O(3) for 6 hr and then sacrificed 9 or 32 hr after APAP administration (1 or 24 hr after O(3) exposure, respectively). Animals euthanized at 32 hr were given 5-bromo-2-deoxyuridine 2 hr before sacrifice to identify hepatocytes undergoing reparative DNA synthesis. Saline-treated mice exposed to either air or O(3) had no liver injury. All APAP-treated mice developed marked centrilobular hepatocellular necrosis that increased in severity with time after APAP exposure. O(3) exposure increased the severity of APAP-induced liver injury as indicated by an increase in necrotic hepatic tissue and plasma alanine aminotransferase activity. O(3) also caused an increase in neutrophil accumulation in livers of APAP-treated animals. APAP induced a 10-fold increase in the number of bromodeoxyuridine-labeled hepatocytes that was markedly attenuated by O(3) exposure. Gene expression analysis 9 h after APAP revealed differential expression of genes involved in inflammation, oxidative stress, and cellular regeneration in mice treated with APAP and O(3) compared to APAP or O(3) alone, providing some indications of the mechanisms behind the APAP and O(3) potentiation. These results suggest that acute exposure to near ambient concentrations of this oxidant air pollutant may exacerbate drug-induced liver injury by delaying hepatic repair.[Aibo DI et al; Toxicol Sci 115 (1): 267-85 (2010)] Full text: PMC2855356 Abstract: PubMed
        A case of a 22-year-old man who developed fulminant hepatic failure 3 days after an intentional acetaminophen overdose /is presented/. The patient had a history of a seizure disorder for which he was taking phenytoin. The acetaminophen level at presentation was in the nontoxic range. Emergent liver transplantation was performed 4 days after the ingestion. ... Abstract: PubMed
        Suchin S et al; Dig Dis Sci 50 (10): 1836-8 (2005)
        Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 mL hydrochloric acid (HCl) 0.1 M and/or an i p injection of the cholinomimetic, acetyl-beta-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 hr after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxicity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy. Abstract: PubMed
        Rainsford KD, Whitehouse MW; Inflammopharmacology 14 (3-4): 150-4 (2006)
        The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. ... Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 ug subcutaneously twice daily within one hour before the morning and evening meals. ... Abstract: PubMed
        Bray G; Am J Health Syst Pharm 63 (5): 411-8 (2006)
        Both fenoldopam and acetaminophen undergo conjugation with sulfate in humans. The present study was undertaken to determine if a metabolic interaction exists between these two compounds in humans. Twelve healthy male volunteers participated in a single-dose crossover study with 100 mg fenoldopam (capsule) alone or in combination with 1000 mg acetaminophen. The effects of chronic acetaminophen dosing (1000 mg three times/day for 7 days) on a single 100 mg tablet of fenoldopam were studied in a second crossover study in seven additional volunteers. Concomitant dosing with fenoldopam with acetaminophen resulted in increases in peak fenoldopam plasma concentration and AUC after both single (+32% and +50%, respectively) and chronic (+73% and +66%, respectively) acetaminophen dosing. Decreases in peak plasma concentrations and AUC for fenoldopam's sulfated metabolites were seen in both studies. These findings indicate a metabolic basis for the interaction between fenoldopam and acetaminophen, presumably through a competition for inorganic sulfate. Abstract: PubMed
        Ziemniak J et al; Clin Pharmacol Ther 41 (3): 275-81(1987)
        This study examined the effect of metyrapone on the elimination rate of acetaminophen and on the apparent formation rate of acetaminophen metabolites in man. Metyrapone treatment, 1.5 g, increased the half-life of acetaminophen, decreased the fraction of the dose recovered in the urine as the glucuronide and increased the fraction of the dose recovered in urine as the sulfate and mercapturate conjugates. The apparent rate constant for the formation of acetaminophen glucuronide was significantly decreased by metyrapone while the apparent rate constants for the formation of the sulfate and mercapturic acid metabolites were unchanged or slightly increased, respectively. These data indicate that metyrapone inhibits acetaminophen glucuronidation and possibly enhances the oxidation of acetaminophen to its quantitatively minor yet highly toxic reactive metabolite. Abstract: PubMed
        Galinsky R et al; Eur J Clin Pharmacol 33 (4): 391-6 (1987)
        Acetaminophen metabolism and clearance after a single 1 g oral dose of the drug was investigated in 12 healthy men, six of whom were cigarette smokers, and in six men who were receiving anticonvulsant drugs for epilepsy. The 12 healthy subjects were studied before and after 1 wk of pretreatment with cimetidine (1 gm/day) or sulfinpyrazone (800 mg/day). There was no significant difference in acetaminophen clearance (ClAP) between nonsmokers and smokers; cimetidine pretreatment had no effect on ClAP. Neither cigarette smoking nor cimetidine pretreatment had a significant effect on any of the metabolic pathways of acetaminophen. In contrast, sulfinpyrazone pretreatment increased ClAP by 23% (from 5.70 +/- 0.21 to 7.00 +/- 0.39 mL/min/kg) and ClAP was 46% greater in the epileptic subjects who received anticonvulsant drugs than in the control group (8.32 +/- 0.45 and 5.70 +/- 0.21 mL/min/kg). In both cases the increase in ClAP was a result of induction of acetaminophen glucuronidation and oxidation; clearance of the glucuronic acid conjugate was 26% and 59% greater and clearance of the glutathione-derived conjugates (reflecting the activity of the oxidative pathway) was 43% and 60% greater in the groups given sulfinpyrazone and anticonvulsants, respectively. Abstract: PubMed
        Miners J et al; Clin Pharmacol Ther 35 (4): 480-6 (1984)
        To investigate a possible pharmacokinetic interaction between zidovudine and paracetamol. Six patients with AIDS took both zidovudine (AZT; 1000-1200 mg/day) and paracetamol (500 mg every 6 hr) for 7 days. Pharmacokinetic monitoring was performed on day 0 (AZT alone) and after 7 days of combined use of paracetamol and AZT. Combined use of paracetamol and AZT did not result in a significant change in any of the calculated pharmacokinetic parameters of AZT or its primary metabolite AZT-glucuronide. In addition, paracetamol pharmacokinetic parameters at day 7 did not differ from those usually reported in the literature. Short-term, combined use of paracetamol and AZT does not lead to a change in the pharmacokinetics of either AZT or paracetamol. The effect of long-term use of this combination remains unknown. A recent case report of AZT-induced paracetamol hepatotoxicity indicates that clinicians should still be aware of potential drug toxicity when prescribing both AZT and paracetamol. Abstract: PubMed
        Burger D et al; Neth J Med 44 (5): 161-5 (1994)
        Ibuprofen and acetaminophen are frequently alternated or simultaneously used to treat fever or pain in children, while the evidence for the safety of such a combination is lacking. In this study, we analyzed the association of acute kidney injury (AKI) with ibuprofen, acetaminophen, and the combination of both drugs in children (0-12 years) by using the FDA Adverse Event Reporting System (AERS) database between January 2004 and June 2012. Adverse event reports in children aged 0 to =12 years were included in the study. Cases were defined as reports of AKI according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology, non-cases as all other reports. Exposure categories were divided into three index groups: two groups where ibuprofen or acetaminophen were used in absence of one another and another group where both drugs were used concomitantly. There was also a reference group, in which neither ibuprofen nor acetaminophen was used. These index groups were compared with the reference group using reporting odds ratios (RORs). In total, 47,803 reports were included in the study. After adjusting for year of reporting, age, and sex, the ROR for an AKI in children who used only ibuprofen or acetaminophen compared with children who used neither ibuprofen nor acetaminophen was 2.14 (95 % CI: 1.59-2.88) and 1.53 (95 % CI: 1.18-1.97), respectively, while the adjusted ROR was 4.01 (95 % CI: 2.96-5.43) when both drugs were concomitantly used. The results illustrate that the concomitant use of ibuprofen and acetaminophen in children might be associated with increased risk of AKI.[Yue Z et al; Eur J Clin Pharmacol. 2014 Jan 21. Abstract: PubMed
        Epub ahead of print]
        Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15?mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.[Ganetsky M et al; J Clin Pharmacol. 53 (4): 413-20 (2013)] Full text: PMC4383763 Abstract: PubMed
        Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in industrialized countries. Understanding the mechanisms of APAP-induced liver injury as well as other forms of sterile liver injury is critical to improve the care of patients. Recent studies demonstrate that danger signaling and inflammasome activation play a role in APAP-induced injury. The purpose of these investigations was to test the hypothesis that benzyl alcohol (BA) is a therapeutic that protects against APAP-induced liver injury via modulation of danger signaling. Main Results. APAP-induced liver injury was dependent in part on TLR-9 and receptor for advanced glycation endproducts (RAGE) signaling. BA limited liver injury over a dose range of 135-540 ug/g body weight or when delivered as a pre-, concurrent, or post-APAP therapeutic. Furthermore, BA abrogated APAP-induced cytokines and chemokines as well as high mobility group box-1 release. Moreover, BA prevented APAP-induced inflammasome signaling as determined by IL-1beta, IL-18 and caspase-1 cleavage in liver tissues. Interestingly, the protective effects of BA on limiting liver injury and inflammasome activation were dependent on TLR4 signaling, but not TLR2 or Cluster of differentiation 14 (CD14). Cell type specific knockouts of TLR4 were utilized in order to further determine the protective mechanisms of BA. These studies found that TLR4 expression specifically in myeloid cells (LyzCre-tlr4-/-) were necessary for the protective effects of BA. Conclusion: BA protects against APAP-induced acute liver injury and reduced inflammasome activation in a TLR4-dependent manner. BA may prove to be a useful adjunct in the treatment of APAP and other forms of sterile liver injury.[Cai C et al; Hepatology. 2014 May 3. doi: 10.1002/hep.27201. Abstract: PubMed
        Epub ahead of print]

      7. Toxicity Summary

        IDENTIFICATION AND USE: Acetaminophen is an odorless compound with a slightly bitter taste. It is a common analgesic and antipyretic agent used for the relief of fever as well as aches and pains associated with many conditions. HUMAN EXPOSURE AND TOXICITY: Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression, stupor, hypothermia, marked prostration, rapid shallow breathing, rapid weak irregular pulse, low blood pressure, and circulatory failure. When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage and/or cardiotoxic effects usually do not become apparent until 2-4 days after ingestion of the drug. Other symptoms of acute poisoning include cerebral edema and nonspecific myocardial depression. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days. Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Hypoglycemia, which can progress to coma have been reported in patients ingesting toxic doses of acetaminophen. Low prothrombin levels and thrombocytopenia have been reported in patients with acetaminophen poisoning. Skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions also have been reported. For use anytime during pregnancy, 781 exposures were recorded, and possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found. There is inadequate evidence in humans for the carcinogenicity of acetaminophen. ANIMAL TOXICITY STUDIES: There is inadequate evidence in experimental animals for the carcinogenicity of acetaminophen. In rats fasted 24 hours and given a single dose of acetaminophen (2 g/kg) by gavage, liver necrosis around the central vein was noted at 9-12 hours and was much more extensive at 24 hours after treatment. In mice after dietary exposure to acetaminophen up to 6400 mg/kg daily for 13 weeks hepatotoxicity, organ weight changes and deaths were observed. Cats are particularly susceptible to acetaminophen intoxication, developing more diffuse liver changes, while hepatic centrilobular lesions found in dogs. High doses of acetaminophen caused testicular atrophy and delay in spermiogenesis in mice. Furthermore, reductions in the fertility and neonatal survival in mice were seen in the F0 generation and decreases in F1 pup weights were found at acetaminophen dose 1430 mg/kg. Acetaminophen was not mutagenic in Salmonella typhimurium assay with or without metabolic activation in six strains: TA1535, TA1537, TA1538, TA100, TA97 and TA98. In vitro and animal data indicate that small quantities of acetaminophen are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible for acetaminophen-induced liver necrosis in cases of overdose. Excipients found in liquid formulations of acetaminophen may decrease its liver toxicity. ECOTOXICITY STUDIES: Daphnia magna was the most susceptible among the test organisms to the environmental effects of acetaminophen. Acetaminophen has recently been identified as a promising snake toxicant to reduce brown tree snake populations on Guam, while posing only the minimal risks to non-target rodents, cats, pigs and birds.
        Oral, mouse: LD50 = 338 mg/kg; Oral, rat: LD50 = 1944 mg/kg. Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with glucuronic acid and, to a lesser extent, sulfuric acid. Conjugates are then excreted by the kidneys. Only a small portion is excreted in unchanged in urine or oxidized via the hepatic cytochrome P450 enzyme system (CYP2E1). Metabolism via CYP2E1 produces a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). The toxic effects of acetaminophen are due to NAPQI, not acetaminophen itself nor any of the major metabolites. At therapeutic doses, NAPQI reacts with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is excreted by the kidneys. High doses of acetaminophen may cause glutathione depletion, accumulation of NAPQI and hepatic necrosis. The maximum daily dose of acetaminophen is 4 g. Liver failure has been observed at doses as low as 6 g per day. As such, the maximum daily and single dose of acetaminophen is currently being reviewed in some countries. N-acetyl-cysteine, a precursor of glutathione, may be administered in the event of acetaminophen toxicity.

      8. Antidote and Emergency Treatment

        Emergency and supportive measures. Spontaneous vomiting may delay the oral administration of antidote or charcoal and can be treated with metoclopramide or a serotonin receptor antagonist such as ondansetron. Provide general supportive care for hepatic or renal failure if it occurs. Emergency liver transplant may be necessary for fulminant hepatic failure. Encephalopathy, metabolic acidosis, hypoglycemia, and a progressive rise in the prothrombin time are indications of severe liver injury.
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 70
        Specific drugs and antidotes: Acute single ingestion. If the serum level fall above the upper ("probably toxicity") line on the nomogram or if stat serum levels are not immediately available, initiate antidotal therapy with N-acetylcysteine (NAC). the effectiveness of NAC depends on early treatment, before the toxic metabolite accumulates; it is of maximal benefit if started within 8-10 hours and of diminishing value after 12-16 hours; however, treatment should not be withheld even if the delay is 24 hours or more. If vomiting interferes with or threatens to delay oral acetylcysteine administration, give the NAC IV. If the serum level falls between the "possible toxicity" and "probably toxicity" nomogram lines, strongly consider giving NAC, especially if the patient is at increased risk for toxicity - for example, if the patient is alcoholic, is taking a drug that induces CYP2E1 activity (eg, isoniazid), or has taken multiple or subacetate overdoses - or if the time of ingestion is uncertain or unreliable. Many national and international guidelines sue the "possible toxicity" line as the threshold for treating all patients with acute acetaminophen overdose. If the serum level falls below the lower nomogram line, treatment is generally not indicated unless the time of ingestion is uncertain or the patient is considered to be at particularly high risk. NOTE: After ingestion of extended-release tablets, which are designed for prolonged absorption, there may be a delay before the peak acetaminophen level is reached. This can also occur after co-ingestion of drugs that delay gastric emptying, such as opioids and anticholinergics. In such circumstances, repeat the serum acetaminophen level at 8 hours and possible 12 hours. In such cases, it may be prudent to initiate NAC therapy before 8 hours while waiting for subsequent levels.
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 71
        Specific drugs and antidotes: Chronic or repeated acetaminophen ingestions. Patients may give a history of several doses taken over 24 hour or more, in which case the nomogram cannot accurately estimate the risk for hepatotoxicity. In such cases, we advise NAC treatment if the amount ingested was more tha 200 mg/kg within a 24 hour persons, 150 mg/kg/day for 2 days, or 100 mg/kg/day for 3 days or more; if the liver enzymes are elevated; if there is detectable acetaminophen in the serum; or if the patient falls within a high-risk group. Treatment may be stopped 24 hours after the last dose of acetaminophen if the liver enzymes and PT/INR are normal.
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
        Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Although activated charcoal adsorbs some of the orally administered antidote N-acetylcysteine, this effect is not considered clinically important. Do not administer charcoal if more than 3-4 hours has passed since ingestion unless delayed absorption is suspected ... .
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
        Enhanced elimination. Hemodialysis effectively removes acetaminophen from the blood but is not generally indicated because antidotal therapy is so effective. Dialysis should be considered for massive ingestions with very high levels (eg, > 1000 mg/L) complicated by coma and/or hypotension.
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 72
        Treatment /of overdosage/ consists of two categories. First, the patient who presents early is treated to reduce or prevent acetaminophen-induced injury by the early administration of acetylcysteine. The late-presenting patient is treated to limit organ injury that arises from acetaminophen toxicity.
        Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 735
        The term preventive is applied to the early treatment of patients with acute overdosage. Hepatic injury can be prevented in nearly all patients treated with acetylcysteine within 8 to 10 hours of an acute ingestion, regardless of the magnitude of the acetaminophen level. Although the mortality is low (11 of 2540 patients, or 0.43%), early treatment is imperative, as no deaths occurred in this same series in patients treated before 16 hours postingestion. The data indicate that acetylcysteine also has some therapeutic effect for patients who present 10 to 24 hours after ingestion, although its efficacy diminishes as the time to treatment increases. Some suggestion has been made that treatment performed at even as late as 36 hours may have some benefit. Therefore, all patients with a single acute ingestion of acetaminophen whose serum acetaminophen level falls above the treatment line should be treated with acetylcysteine.
        Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 584
        If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack-Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line.
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
        /SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
        Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
        /SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
        Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
        /SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
        Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

      9. Human Toxicity Excerpts

        /HUMAN EXPOSURE STUDIES/ Three hundred and seven cases of liver injury associated with acetaminophen use were reported to the US Food and Drug Administration (FDA) from January 1998 to July 2001. Sixty percent of these adverse events were categorized as severe life-threatening injury with liver failure (category 4); 40% of patients died. Review of these case reports indicates that use of higher than recommended daily dosages of acetaminophen results in adverse hepatotoxic effects more often than use of recommended dosages.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211
        /HUMAN EXPOSURE STUDIES/ The Rocky Mountain Poison and Drug Center reported the results of a nationwide study on acetaminophen overdose during pregnancy involving 113 women. Of the 60 cases that had appropriate laboratory and pregnancy outcome data, 19 occurred in the 1st trimester, 22 during the 2nd trimester, and 19 during the 3rd trimester. In those cases with a potentially toxic serum level of acetaminophen, early treatment with N-acetylcysteine was statistically associated with an improved pregnancy outcome by lessening the incidence of spontaneous abortion and fetal death. Only one congenital anomaly was observed in the series and that involved a 3rd trimester overdose with nontoxic maternal acetaminophen serum levels.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 9
        /HUMAN EXPOSURE STUDIES/ Paracetamol (acetaminophen) is a widely used analgesic drug. It interacts with various enzyme families including cytochrome P450 (CYP), cyclooxygenase (COX), and nitric oxide synthase (NOS), and this interplay may produce reactive oxygen species (ROS). ... The effects of paracetamol on prostacyclin, thromboxane, nitric oxide (NO), and oxidative stress in four male subjects who received a single 3 g oral dose of paracetamol /was investigated/. Thromboxane and prostacyclin synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1 a , respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-prostaglanding F2 a was measured to assess oxidative stress. Plasma oleic acid oxide (cis-EpOA) was measured as a marker of cytochrome P450 activity. Upon paracetamol administration, prostacyclin synthesis was strongly inhibited, while NO synthesis increased and thromboxane synthesis remained almost unchanged. Paracetamol may shift the COX-dependent vasodilatation/vasoconstriction balance at the cost of vasodilatation. This effect may be antagonized by increasing endothelial NO synthesis. High-dosed paracetamol did not increase oxidative stress. At pharmacologically relevant concentrations, paracetamol did not affect NO synthesis/bioavailability by recombinant human endothelial NOS or inducible NOS in rat hepatocytes. /It was concluded/ that paracetamol does not increase oxidative stress in humans.[Trettin A et al; Oxid Med Cell Longev. 2014;2014:212576. doi: 10.1155/2014/212576. Epub 2014 Mar 31] Full text: PMC3988730 Abstract: PubMed
        /HUMAN EXPOSURE STUDIES/ ... Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.[Possamai LA et al; Crit Care Med 41 (11): 2543-50 (2013)] Full text: PMC3939768 Abstract: PubMed
        /SIGNS AND SYMPTOMS/ Acetaminophen toxicity may result from a single toxic dose, from repeated ingestion of large doses of acetaminophen (e.g., 7.5-10 g daily for 1-2 days), or from chronic ingestion of the drug. Dose-dependent, hepatic necrosis is the most serious acute toxic effect associated with overdosage and is potentially fatal.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        /SIGNS AND SYMPTOMS/ Very high levels of acetaminophen can cause lactic acidosis and altered mental status by uncertain mechanisms, probably involving mitochondrial dysfunctin.
        OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69
        /SIGNS AND SYMPTOMS/ Symptoms ... of acute poisoning ... both metabolic acidosis & metabolic alkalosis have been noted; cerebral edema & nonspecific myocardial depression have also occurred. Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area.
        Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 704
        /SIGNS AND SYMPTOMS/ Acetaminophen toxicity usually involves 4 phases: 1) anorexia, nausea, vomiting, malaise, and diaphoresis (which inappropriately may prompt administration of additional acetaminophen); 2) resolution of phase-1 manifestations and replacement with right upper quadrant pain or tenderness, liver enlargement, elevated bilirubin and hepatic enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria; 3) anorexia, nausea, vomiting, and malaise recur (usually 3-5 days after initial symptom onset) and signs of hepatic failure (e.g., jaundice, hypoglycemia, coagulopathy, encephalopathy) and possibly renal failure and cardiomyopathy develop; and 4) recovery or progression to fatal complete liver failure.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        /SIGNS AND SYMPTOMS/ Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. Unlike salicylates, acetaminophen does not usually cause acid/base changes in toxic doses. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression; stupor; hypothermia; marked prostration; rapid, shallow breathing; rapid, weak, irregular pulse; low blood pressure; and circulatory failure. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal asphyxial seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        /SIGNS AND SYMPTOMS/ When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage usually does not become apparent until 2-4 days after ingestion of the drug. Transient azotemia and renal tubular necrosis have been reported in patients with acetaminophen poisoning; renal failure is often associated with fatality. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Maximum cardiotoxic effects of these drugs appear to be delayed in a manner similar to hepatotoxic effects. Hypoglycemia, which can progress to coma, and metabolic acidosis have been reported in patients ingesting toxic doses of acetaminophen and cerebral edema occurred in one patient.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2210
        /SIGNS AND SYMPTOMS/ Low prothrombin levels have been reported in patients with acetaminophen poisoning and in one patient fatal GI hemorrhage was attributed to hypoprothrombinemia. Thrombocytopenia also has been reported. Toxic doses of p-aminophenol derivatives may produce skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2210
        /SIGNS AND SYMPTOMS/ In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur. Plasma acetaminophen levels > 300 ug/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 ug/mL or < 37.5 ug/mL at 12 hours after ingestion. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
        /SIGNS AND SYMPTOMS/ The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal. Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. ... Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers. Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.
        US FDA; FDA Drug Safety Communication: FDA Warns of Rare but Serious Skin Reactions with the Pain Reliever/Fever Reducer Acetaminophen (8/1/2013). Available from, as of March 6, 2014: http://www.fda.gov/drugs/drugsafety/ucm363041.htm
        /CASE REPORTS/ ... A 45-year-old white man weighing 85 kg with asymptomatic HIV, hepatitis B virus, and hepatitis C virus (HCV) infection presented with signs of severe hepatotoxicity: aspartate aminotransferase (AST), 8,581 IU/L; alanine aminotransferase (ALT), 5,433 IU/L; L-lactate dehydrogenase, 13,641 IU/L; and prothrombin international normalized ratio, 2.15. He reported taking acetaminophen 1,000 mg QID /four times a day/ for the previous 4 days and 1,000 mg that morning because of a febrile illness. Immediate administration of continuous IV N-acetylcysteine 150 mg/kg for the first 90 minutes and then 50 mg/kg q4h /every four hours/ for the next 3 days was followed by clinical improvement and a rapid decrease in AST and ALT. AST levels decreased from 8,581 to 42 IU/L within 11 days. Several potential risk factors for acetaminophen hepatotoxicity (ie, chronic alcohol, tobacco, and opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection) were present in this patient. This patient with multiple risk factors and severe hepatotoxicity after therapeutic dosage of acetaminophen was successfully treated with N-acetylcysteine. Abstract: PubMed
        Moling O et al; Clin Ther 28 (5): 755-60 (2006)
        /CASE REPORTS/ /The authors/ report a case of oral acetaminophen toxicity in a term newborn infant successfully treated with a 20 hr intravenous N-acetylcysteine infusion protocol without any adverse effects. This case report supports the use of N-acetylcysteine to treat neonatal acetaminophen toxicity ... Abstract: PubMed
        Walls L et al; J Perinatol 27 (2): 133-5 (2007)
        /CASE REPORTS/ A 3 yr old girl who ingested about thirty five 325 mg tablets of acetaminophen was only moderately ill with serum concn of 94 ug/mL, but showed very high levels of hepatic enzymes. The importance of determining acetaminophen plasma concentration at different times to evaluate plasma half-life is discussed. Abstract: PubMed
        Arena JM et al; Pediatrics 61 (Jan): 68 (1978)
        /CASE REPORTS/ A 3.5 yr old girl with an upper respiratory infection died of an acetaminophen overdose. When the child's temperature remained elevated after treatment with 120 mg every 4 hr for 3 doses, dosage was increased to 720 mg every 3 hr. Over the next 24 hr the patient received 5.04 g. Abstract: PubMed
        Nogen A, Bremmer J; J Pediatr 92 (MAY): 832 (1978)
        /CASE REPORTS/ A 63 yr old man with acute psittacosis had severe hepatic damage after ingesting about 10 g acetaminophen over a 48 hr period. Transaminase levels showed striking elevation, with a serum glutamic-oxaloacetic transaminase level of over 15000 iu/L, and decreased rapidly, consistent with toxic insult. The liver showed severe central necrosis at autopsy. Abstract: PubMed
        Davis AM et al; Am J Med 74 (2): 349 (1983)
        /CASE REPORTS/ An 18-year-old woman, gravida 1, presented at 33 weeks' gestation with signs and symptoms consistent with acute fatty liver of pregnancy and fetal death. Markedly elevated transaminases prompted a search for other etiologies, and acetaminophen toxicity was diagnosed. Liver biopsy revealed acute fatty liver of pregnancy and toxin-induced injury consistent with acetaminophen use. The patient's condition deteriorated, resulting in fulminant hepatic failure and requiring postpartum orthotopic liver transplantation. The combination of acute fatty liver of pregnancy and acetaminophen toxicity resulted in acute liver failure. Attention to clinical and biochemical parameters can lead to diagnosis and management. Abstract: PubMed
        Gill EJ t al; J Reprod Med 47 (7): 584-6 (2002)
        /CASE REPORTS/ A case involving a 22-year-old woman in her 31st week of pregnancy who consumed a 15 g dose /acetaminophen/, followed by a 50 g dose 1 week later /is reported/. Fetal distress was observed 16 hours after the second overdose, as evidenced by complete lack of fetal movements and breathing, a marked decrease in fetal heart rate beat-to-beat variability with no accelerations, and a falling baseline rate. Because of the fetal condition, labor was induced (cesarean section was excluded because of the mothers incipient hepatic failure). Eighty-four hours after the overdose, a 2198 g female infant was delivered with an Apgar scores at 1 and 5 min of 9 and 10, respectively. Except for hypoglycemia, mild respiratory disease, and mild jaundice, the newborn did well. Liver enzymes were always within normal range, and the jaundice was compatible with immaturity. Acetaminophen was not detected in the cord blood. Follow-up examinations of the infant at 6 weeks and again at 6 months were normal. ...Protection against serious or permanent liver damage was probably afforded by the prompt administration of iv N-acetylcysteine.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 9
        /CASE REPORTS/ Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely, acute tubular necrosis or a fixed drug exanthema. /The authors/ present a case of fatal acetaminophen toxicity with postmortem blood concentration 78 ug/mL and unusual clinical features, including a visually striking and massive epidermolysis and rhabdomyolysis, disseminated intravascular coagulation and myocardial ischemia. This case is compared with the most similar previous reports in terms of organ damage, clinical presentation, and cause of death. We conclude that a number of severe patterns of adverse effects to acetaminophen are emerging that were previously greatly underestimated, thus questioning the adequacy of the clinical spectrum traditionally associated with acetaminophen intoxication and leading to the need to review this spectrum and the associated diagnostic criteria. Abstract: PubMed
        De-Giorgio F et al; J Forensic Sci 58 (5): 1397-400 (2013)
        /CASE REPORTS/ Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but life-threatening, severe cutaneous adverse reactions most frequently caused by exposure to drugs. Several reports have associated the use of acetaminophen with the risk of SJS or TEN. A typical interval from the beginning of drug therapy to the onset of an adverse reaction is 1-3 weeks. A 43-year-old woman and a 60-year-old man developed skin lesions within 3 days after administration of acetaminophen for a 3-day period. Rapid identification of the symptoms of SJS and TEN caused by ingestion of acetaminophen enabled prompt withdrawal of the culprit drug. After administration of intravenous immunoglobulin G, both patients recovered fully and were discharged. These two cases of rapidly developed SJS/TEN after ingestion of acetaminophen highlight the possibility that these complications can develop within only a few days following ingestion of over-the-counter medications such as acetaminophen.[Kim EJ et al; Asia Pac Allergy 4 (1): 68-72 (2014)] Full text: PMC3921868 Abstract: PubMed
        /CASE REPORTS/ /The authors/ report the case of a 15-year-old boy, referred to Immunoallergy Department due to four reproducible episodes of anaphylaxis after paracetamol administration, since the age of 8 years. The most severe episode occurred at 12 years, characterized by glottis edema with respiratory distress, hypotension, generalized urticaria and facial edema, immediately after intravenous administration of paracetamol during a post-operatory recovery. He had always and still tolerates ibuprofen; an oral challenge test with meloxicam was negative. Skin prick and intradermal tests with paracetamol were negative. Serum-specific IgE and CAST to paracetamol were also negative. This report provides an alert to health-care professionals regarding the potential severity of reactions occurring within the therapeutic range of this widely used drug. Abstract: PubMed
        Couto M et al; Eur Ann Allergy Clin Immunol 44 (4): 163-6 (2012)
        /CASE REPORTS/ ... A 38-year-old woman whose pregnancy was at 31 weeks' gestational age was evaluated for treatment of an acetaminophen overdose. She was admitted more than 26 hours after taking 35 g of acetaminophen. An emergency cesarean section was performed one hour after admission because of acute fetal distress. A grossly normal, 1,620-g, female infant was delivered and had Apgar scores at 1, 5 and 10 minutes of 0, 0 and 1, respectively, despite the initiation of resuscitation immediately following delivery. Acidosis was noted in the mother during the operation; it was followed by acute hepatorenal failure 16 hours after admission. That resulted in the mother's death 40 hours after admission. The infant also died 34 hours after delivery. Delays in administering the antidote treatment, N-acetylcysteine, after acetaminophen intoxication significantly increase the risk of mortality in both the mother and infant. The development of acidosis carries a poor prognosis in such patients and may necessitate liver transplantation to save the life of the mother.
        Wang PH et al; J Reprod Med 42 (6): 367-71 (1997)
        /CASE REPORTS/ Acetaminophen overdose is the most rapidly growing cause of fulminant hepatic failure in Western countries. Pregnant women are counseled that acetaminophen is safe during pregnancy and an alternative to nonsteroidal anti-inflammatory medications. This report describes a case of acetaminophen overdose during the second trimester of pregnancy with resultant fulminant hepatic failure requiring liver transplantation. The fetus was previable at the time of liver transplantation, and methods to preserve viability during and after transplantation are discussed. Despite the best attempts of the team, the fetus expired. The challenges and outcomes of fulminant hepatic failure in pregnancy are discussed in detail. Abstract: PubMed
        Franko KR et al; Transplant Proc 45 (5): 2063-5 (2013)
        /CASE REPORTS/ ... A 22 year pregnant female presented with abdominal pain and hepatotoxicity after taking supratherapeutic amounts of acetaminophen (APAP) to treat dental pain. The patient denied intentional or acute ingestion of APAP but did admit to taking approximately 8-9 grams of APAP per day for 10-14 days for dental pain. Other cause of hepatotoxicity, including acute fatty liver of pregnancy, were evaluated for and ruled out. She developed fulminant hepatic failure and required liver transplantation which was successful. The pregnancy remained viable through the operation but intrauterine fetal demise occurred 2 weeks later. An MRI of the fetus showed extensive peri-cerebral and intraventricular hemorrhage with extensive periventricular leukomalacia. The degree of morbidity from repeated supratherapeutic ingestions of APAP seen in this case is rare and poorly described in a pregnant patient. There are no prior reports describing the need for liver transplant after repeated supratherapeutic ingestions of APAP during pregnancy. Along with the typical cause of hepatotoxicy several unique pregnancy-related causes also had to be evaluated for. This case highlights the significant morbidity that can occur with even unintentional APAP toxicity and the need to educate patients, especially pregnant patients, of the risk of excessive APAP use.[Thornton SL, Minns AB; J Med Toxicol 8 (2): 176-8 (2012)] Full text: PMC3550237 Abstract: PubMed
        /CASE REPORTS/ A 37-year-old alcoholic presented to hospital with metabolic acidosis, hypoglycemia, hypoprothrombinemia, and markedly elevated SGOT level. Despite the absence of volunteered information, acetaminophen hepatotoxicity was considered the probable cause, and this diagnosis was eventually supported. This combination of findings appears to be highly suggestive of well-established acetaminophen hepatotoxicity and implies that the drug-induced lesion selectively impairs certain hepatocellular functions early in the progression of the injury. Abstract: PubMed
        Black M et al; Dig Dis Sci 27 (4): 370-4 (1982)
        /EPIDEMIOLOGY STUDIES/ In a prospective study of 1529 pregnant women studied in the mid-1970s, acetaminophen was used in the 1st half of pregnancy by 41%. Using a computerized system for stratifying on maternal alcohol and smoking histories, 421 newborns were selected for follow-up. Of this group, 43.5% had been exposed in utero to acetaminophen in the first half of pregnancy. After statistical control of numerous potentially confounding covariates, the data indicated that acetaminophen was not significantly related to child IQ at 4 years of age or to attention variables. Three physical growth parameters (height, weight, and head circumference) were also not significantly related to in utero acetaminophen exposures.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 10
        /EPIDEMIOLOGY STUDIES/ The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 226 of which had 1st trimester exposure to acetaminophen. Although no evidence was found to suggest a relationship to large categories of major or minor malformations, a possible association with congenital dislocation of the hip was found based on three cases. The statistical significance of this association is unknown, and independent conformation is required. For use anytime during pregnancy, 781 exposures were recorded. As with the qualifications expresses for 1st trimester exposure, possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 10
        /EPIDEMIOLOGY STUDIES/ To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure, a prospective observational study in two tertiary liver transplant units /was conducted/. Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.[Possamai LA et al; Crit Care Med 41 (11): 2543-50 (2013)] Full text: PMC3939768 Abstract: PubMed
        /EPIDEMIOLOGY STUDIES/ Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, /the researchers/ evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a single-time-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophen-metabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients. This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminophen-induced ALF.[Court MH et al; Drug Metab Dispos 42 (1): 28-32 (2014)] Full text: PMC3876784 Abstract: PubMed
        /EPIDEMIOLOGY STUDIES/ The understanding of whether the use of acetaminophen and/or antibiotics in early life can cause allergic diseases in later childhood remains inconclusive. The objective of this study was to investigate the temporal relationship between exposure to acetaminophen and/or antibiotics in early life and the development of allergic diseases in later childhood, using two independent birth cohorts derived from the National Health Insurance Research Database (NHIRD) in Taiwan. ... A prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, separately, from the NHIRD /was conducted/. Exposure status of acetaminophen and/or antibiotics and potential confounding factors were included in the analyses. Cox proportional hazards models were applied to determine the temporal relationship between acetaminophen and/or antibiotic exposure and the development of allergic diseases. ... A positive relationship between acetaminophen and/or antibiotic exposure during the 1st year of life and the subsequent development of the three examined allergic diseases (atopic dermatitis, asthma and allergic rhinitis) in the 1998 birth cohort/was observed/, but the observed relationship of drug exposure in the 2003 cohort, especially for atopic dermatitis and asthma, was lower than for those in the 1998 cohort and was not statistically significant. ... Findings /suggest/ evidence that the temporal effect of exposure to acetaminophen and/or antibiotics influences the development of common allergic diseases in later childhood. Further functional studies and/or animal studies are needed to better understand the underlying regulatory mechanisms driving this important clinical and public health issue. Abstract: PubMed
        Wang JY et al; Int J Epidemiol 42 (4): 1087-99 (2013)
        /EPIDEMIOLOGY STUDIES/ Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.[McGill MR et al; J Clin Invest 122 (4): 1574-83 (2012)] Full text: PMC3314460 Abstract: PubMed
        /EPIDEMIOLOGY STUDIES/ Functional outcomes for long-term survivors of acute liver failure (ALF) are not well characterized. The aim of this prospective study was to determine health-related quality of life in long-term adult ALF survivors. Acute Liver Failure Study Group registry participants completed the Centers for Disease Control and Prevention Health-Related Quality of Life 14 and Short Form 36 (SF-36) questionnaires at 1- and/or 2-year follow-up study visits. Responses were compared among ALF subgroups and to those for available general US population controls. Among the 282 adult ALF patients, 125 had undergone liver transplantation (LT), whereas 157, including 95 acetaminophen overdose (APAP) patients and 62 non-APAP patients, were spontaneous survivors (SSs). APAP SS patients reported significantly lower general health scores and more days of impaired mental and physical health, activity limitations due to poor health, pain, depression, and anxiety in comparison with the other groups (P = 0.001). There were no significant differences in coma grade or in the use of mechanical ventilation or intracranial pressure monitoring among the patient groups during their ALF hospitalization, but APAP SSs had significantly higher rates of psychiatric disease and substance abuse (P<0.001). In comparison with the general US population, a greater proportion of the combined SS patients reported fair or poor health and > or =14 days of impaired physical/mental health and activity limitations due to poor health. In addition, a greater proportion of LT recipients reported > or =14 days of impaired physical/mental health. Similar results were observed with the SF-36 across the 3 ALF subgroups and in comparison with population controls. In conclusion, long-term adult survivors of ALF reported significantly lower quality of life scores than US population controls. Furthermore, APAP SS patients reported the lowest quality of life scores, possibly because of higher rates of premorbid psychiatric and substance abuse disorders.[Rangnekar AS et al; Liver Transpl 19 (9): 991-1000 (2013)] Full text: PMC3775983 Abstract: PubMed
        /EPIDEMIOLOGY STUDIES/ Acetaminophen (N-acetyl-p-aminophenol [APAP]) is a widely used medication that can cause hepatotoxicity. We examined characteristics and outcomes of children with chronic exposure (CE) to APAP in the multinational Pediatric Acute Liver Failure (PALF) Study. A total of 895 children enrolled from 2002 to 2009 were grouped by APAP exposure history as: CE (received multiple doses \x{2265}2 days; n = 83), single dose exposure (SE; n = 85), and no exposure (NE; n = 498). CE was the reference group for pairwise comparisons. Median values are shown. Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008). Children in the PALF study with CE had lower bilirubin and higher alanine aminotransferase than those with NE. Outcomes with CE were worse than with SE but better than with NE. Potential reasons for this outcomes advantage over non-APAP-exposed subjects should be explored.[Leonis MA et al; Pediatrics 131 (3): e740-6 (2013)] Full text: PMC3581836 Abstract: PubMed
        /EPIDEMIOLOGY STUDIES/ To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations. Abstract: PubMed
        Watkins PB et al; JAMA 296 (1): 87-93 (2006)
        /SURVEILLANCE/ Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended. Abstract: PubMed
        Larson AM et al; Hepatology 42 (6): 1364-72 (2005)
        /SURVEILLANCE/ In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 9146 newborns had been exposed to acetaminophen during the 1st trimester. A total of 423 (4.6%) major birth defects were observed (416 expected). Specific data were available for six defect categories, including (observed/expected) 87/91 cardiovascular defects, 16/16 oral clefts, 4/7 spina bifida, 30/27 polydactyly, 14/16 limb reduction defects, and 16/22 hypospadias. These data do not support an association between the drug and the defects.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 10
        /SURVEILLANCE/ Atopic Eczema (AE) is a chronic inflammatory skin disease that affects children and adults, and alters quality of life. Previous studies have suggested several socio-demographic and environmental factors related to the prevalence of AE and other allergic diseases, including acetaminophen use. In the present study, ... the rates of isolated AE, AE associated with asthma and AE associated with rhinitis among 13- to 14-year-old Spanish adolescents and the level of association of these conditions with the use of acetaminophen /has been reported/. ... Spanish data from a cross-sectional Phase 3 study within ISAAC /were analyzed/. A total of 28,717 adolescents completed the Phase 3 written questionnaire by answering questions for acetaminophen use and on asthma, rhinitis and AE symptoms. ... An association /has been observed/ between acetaminophen use and AE among the adolescents who had used acetaminophen in the previous month. Furthermore, the prevalence rate increased with the number of allergic processes: for AE alone, the adjusted Prevalence Ratio (aPR) was 1.81 and for AE associated with rhinitis or with asthma, aPRs were 2.20 and 3.03, respectively. /The authors/ conclude that acetaminophen use in childhood may be an important factor associated with development and/or maintenance of AE and other allergic diseases. Abstract: PubMed
        Suarez-Varela MM et al; Iran J Allergy Asthma Immunol 12 (2): 115-23 (2013)
        /SURVEILLANCE/ Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children, /the researchers/ studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. To ascertain outcome information /the researchers/ used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. /The researchers/ estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < 0.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders /the researchers/ evaluated. Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed. Abstract: PubMed
        Liew Z et al; JAMA Pediatr 168 (4):313-20 (2014)
        /BIOMONITORING/ Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies.[Antoine DJ et al; Hepatology 58 (2): 777-87 (2013)] Full text: PMC3842113 Abstract: PubMed
        /BIOMONITORING/ Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity. HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78). HMGB1 (total; 15.4 + or - 1.9 ng/mL, p<0.01, acetylated; 5.4 + or - 2.6 ng/mL, p<0.001), cK18 (5649.8 + or - 721.0U/L, p<0.01), and FL-K18 (54770.2 + or - 6717.0U/L, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R(2)=0.60 and 0.58, respectively, p<0.0001) and prothrombin time (R(2)=0.62 and 0.71, respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King's College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death. K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.[Antoine DJ et al; J Hepatol 56 (5): 1070-9 (2012)] Full text: PMC4127883 Abstract: PubMed
        /BIOMONITORING/ Acetaminophen (APAP) overdose is a very common cause of drug overdose and acute liver failure in the US and Europe. Mechanism-based biomarkers of APAP toxicity have the potential to improve the clinical management of patients with large-dose ingestions of APAP. The current approach to the management of APAP toxicity is limited by imprecise and time-constrained risk assessments and late-stage markers of liver injury. A recent study of 'low-risk' APAP overdose patients who all received treatment with N-acetylcysteine found that cell death biomarkers were more sensitive than alanine aminotransferase (ALT) and APAP concentrations in predicting the development of acute liver injury. The data suggest a potential role for new biomarkers to identify 'low-risk' patients following APAP overdose. However, a practical and ethical consideration that complicates predictive biomarker research in this area is the clinical need to deliver antidote treatment within 10 h of APAP overdose. The treatment effect and time-dependent nature of N-acetylcysteine treatment must be considered in future 'predictive' toxicology studies of APAP-induced liver injury.[James LP et al; Expert Rev Gastroenterol Hepatol 7 (6): 509-12 (2013)] Full text: PMC4124995 Abstract: PubMed
        /ALTERNATIVE and IN VITRO TESTS/ Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, X(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury.[Court MH et al; J Pharmacol Exp Ther 345 (2): 297-307 (2013)] Full text: PMC3629801 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ The toxicity of acetaminophen is closely linked to the drug's metabolism. With therapeutic dosing, acetaminophen is metabolized principally by sulfate and glucuronide conjugation. Small amounts (5-10%) usually are oxidized by cytochrome P-450 (CYP)-dependent pathways (mainly CYP2E1 and CYP3A4) to a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxified by glutathione and eliminated in urine and/or bile, and any remaining toxic metabolite may bind to hepatocytes and cause cellular necrosis. Because of the relatively small amount of NAPQI usually formed and the adequate supply of glutathione that usually is present in the body, acetaminophen generally has an excellent safety profile. However, with acetaminophen overdosage and occasionally with usual dosages in susceptible individuals (e.g., those with nutritional (malnutrition) or drug interactions, those consuming alcohol chronically, those with predisposing medical conditions, those with a genetic metabolic predisposition), hepatotoxic concentrations of NAPQI may accumulate.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        /OTHER TOXICITY INFORMATION/ Because severe liver toxicity and death have occurred in children who received multiple excessive doses of acetaminophen as part of therapeutic administration (i.e., with therapeutic intent), parents or caregivers should be instructed to use weight-based dosing for acetaminophen, to use only the calibrated measuring device provided with the particular acetaminophen formulation for measuring dosage, to ensure that the correct number of tablets required for the intended dose is removed from the package, and not to exceed the recommended daily dosage because serious adverse effects could result. Parents also should be cautioned not to use other acetaminophen-containing products (e.g., some cold and cough products) concomitantly with acetaminophen in children because of the potential for overdoses.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2208

      10. Non-Human Toxicity Excerpts

        /LABORATORY ANIMALS: Acute Exposure/ ... Acetaminophen was administered to 4 adult cats. A marked degree of cyanosis was seen in these animals within 4 hr after administration of single tablet containing 325 mg ... due to hypoxia associated with conversion of hemoglobin to methemoglobin. In addition, anemia, hemoglobinuria, and icterus were eventually seen in the cats. Hemolysis of red blood cells was responsible for development of anemia and hemoglobinuria. Icterus was attributed to both lysis of erythrocytes and hepatic necrosis. Facial edema was also observed in 3 of the 4 experimental cats.
        Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 304
        /LABORATORY ANIMALS: Acute Exposure/ Postmitochondrial supernatants isolated from the livers of mature rats (3-6 mo old) 2 hr or more after admin of a single large oral dose of paracetamol (800 mg/kg) showed rapid rates of lipid peroxidation. In similar expt with old rats (27-30 mo old) the time between admin of paracetamol and the onset of lipid peroxidation was much longer, up to 6 hr. Abstract: PubMed
        Barber DJ et al; Toxicol Lett 15 (4): 283 (1983)
        /LABORATORY ANIMALS: Acute Exposure/ Male Wistar rats were fasted 24 hr and administered a single dose of paracetamol/water suspension (2 g paracetamol/kg) by gavage. Rats were killed, and liver and blood samples taken at 0, 6, 9, 12, and 24 hr post paracetamol administration. Hepatic reduced glutathione levels were lowered within 6 hr after paracetamol treatment, and remained so until returning to control levels at 12-24 hr. Serum glutamate pyruvate transaminase (SGPT) levels were increased from control (n= 7) levels of 30-40 mU/mL to 700-3000 mU/mL at 24 hr after paracetamol administration. Blood glucose concentrations of paracetamol treated rats (n= 13) were 5.85 +/- 0.50 mM compared to the control values of 5.28 +/- 0.36 mM. Based on trypan blue exclusion, paracetamol-induced necrosis around the central vein was noted at 9-12 hr and was much more extensive at 24 hr after treatment. A concurrent activation of glycogen phosphorylase in perivenous hepatocytes and an increase in periportal hepatocyte glycogen content was observed at 12 hr post treatment. Abstract: PubMed
        Jepson MA et al; Toxicology 47 (3): 325-37 (1987)
        /LABORATORY ANIMALS: Acute Exposure/ Acetaminophen ... an analgesic and antipyretic, is without known ocular side effects, with the exception that in genetically very special mice it can cause irreversible opacification of the anterior portion of the lens when a large dose is given ip.
        Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 32
        /LABORATORY ANIMALS: Acute Exposure/ The effect of aging on hepatic pharmacokinetics and the degree of hepatotoxicity following a toxic dose of acetaminophen /were investigated/. Young and old male Fischer 344 rats were treated with 800 mg/kg acetaminophen (young n = 8, old n = 5) or saline (young n = 9, old n = 9). Serum measurements showed old rats treated with acetaminophen had significantly lower serum alanine aminotransferase and higher acetaminophen and acetaminophen glucuronide levels and creatinine, compared with acetaminophen treated young rats (p < .05). Immunoblotting and activity assays showed old saline-treated rats had twofold lower cytochrome P450 2E1 activity and threefold higher NAD(P)H quinone oxireductase 1 protein expression and activity than young saline-treated rats (p < .05), although Nrf2, glutathione cysteine ligase-modulatory subunit, glutathione cysteine ligase-catalytic subunit, and cytochrome P450 2E1 protein expressions were unchanged. Primary hepatocytes isolated from young rats treated with 10 mM acetaminophen had lower survival than those from old rats (52.4% + or - 5.8%, young; 83.6% + or - 1.7%, old, p < .05). The pharmacokinetic changes described may decrease susceptibility to acetaminophen-induced hepatotoxicity but may increase risk of nephrotoxicity in old age. Abstract: PubMed
        Mach J et al; J Gerontol A Biol Sci Med Sci 69 (4): 387-97 (2014)
        /LABORATORY ANIMALS: Acute Exposure/ The mechanism by which acetaminophen (APAP) causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD) compared to male C57BL/6 mice in order to identify the cause(s) of sensitivity. Furthermore, ... mice that are either heterozygous (HZ) or null (KO) for glutamate cysteine ligase modifier subunit (Gclm), in order to titrate the toxicity relative to wild-type (WT) mice /were used/. Gclm is important for efficient de novo synthesis of glutathione (GSH). APAP (300 mg/kg, ip) or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 hr. Male mice showed marked elevation in serum alanine aminotransferase by 6 hr. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP-protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. /It was concluded/ that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.[Mohar I et al; Redox Biol 2: 377-87 (2014)] Full text: PMC3926121 Abstract: PubMed
        /LABORATORY ANIMALS: Acute Exposure/ Acetaminophen (APAP) is metabolized in the liver to N-acetyl-p-benzoquinone imine (NAPQI), an electrophilic metabolite known to bind liver proteins resulting in hepatotoxicity. Mammalian thioredoxin reductase (TrxR) is a cellular antioxidant containing selenocysteine (Sec) in its C-terminal redox center, a highly accessible target for electrophilic modification. In the present study, we determined if NAPQI targets TrxR. Hepatotoxicity induced by APAP treatment of mice (300 mg/kg, i.p.) was associated with a marked inhibition of both cytosolic TrxR1 and mitochondrial TrxR2 activity. Maximal inhibition was detected at 1 and 6 hr post-APAP for TrxR1 and TrxR2, respectively. In purified rat liver TrxR1, enzyme inactivation was correlated with the metabolic activation of APAP by cytochrome P450, indicating that enzyme inhibition was due to APAP-reactive metabolites. NAPQI was also found to inhibit TrxR1. NADPH-reduced TrxR1 was significantly more sensitive to NAPQI (IC50 = 0.023 uM) than the oxidized enzyme (IC50 = 1.0 uM) or a human TrxR1 Sec498Cys mutant enzyme (IC50 = 17 uM), indicating that cysteine and selenocysteine residues in the redox motifs of TrxR are critical for enzyme inactivation. This is supported by our findings that alkylation of reduced TrxR with biotin-conjugated iodoacetamide, which selectively reacts with selenol or thiol groups on proteins, was inhibited by NAPQI. LC-MS/MS analysis confirmed that NAPQI modified cysteine 59, cysteine 497, and selenocysteine 498 residues in the redox centers of TrxR, resulting in enzyme inhibition. In addition to disulfide reduction, TrxR is also known to mediate chemical redox cycling. We found that menadione redox cycling by TrxR was markedly less sensitive to NAPQI than disulfide reduction, suggesting that TrxR mediates these reactions via distinct mechanisms. These data demonstrate that APAP-reactive metabolites target TrxR, suggesting an additional mechanism by which APAP induces oxidative stress and hepatotoxicity.[Jan YH et al; Chem Res Toxicol 27 (5): 882-94 (2014)] Full text: PMC4033643 Abstract: PubMed
        /LABORATORY ANIMALS: Acute Exposure/ Stem cell-derived tyrosine kinase (STK) is a transmembrane receptor reported to play a role in macrophage switching from a classically activated/proinflammatory phenotype to an alternatively activated/wound repair phenotype. In the present studies, STK-/- mice were used to assess the role of STK in acetaminophen-induced hepatotoxicity as evidence suggests that the pathogenic process involves both of these macrophage subpopulations. In wild type mice, centrilobular hepatic necrosis and increases in serum transaminase levels were observed within 6 hr of acetaminophen administration (300 mg/kg, i.p.). Loss of STK resulted in a significant increase in sensitivity of mice to the hepatotoxic effects of acetaminophen and increased mortality, effects independent of its metabolism. This was associated with reduced levels of hepatic glutathione, rapid upregulation of inducible nitric oxide synthase, and prolonged induction of heme oxygenase-1, suggesting excessive oxidative stress in STK-/- mice. F4/80, a marker of mature macrophages, was highly expressed on subpopulations of Kupffer cells in livers of wild type, but not STK-/- mice. Whereas F4/80 macrophages rapidly declined in the livers of wild type mice following acetaminophen intoxication, they increased in STK-/- mice. In wild type mice hepatic expression of tumor necrosis factor (TNF)-a, interleukin (IL)-1beta, and IL-12, products of classically activated macrophages, increased after acetaminophen administration. Monocyte chemotactic protein-1 (MCP-1) and its receptor, CCR2, as well as IL-10, mediators involved in recruiting and activating anti-inflammatory/wound repair macrophages, also increased in wild type mice after acetaminophen. Loss of STK blunted the effects of acetaminophen on expression of TNFa, IL-1beta, IL-12, MCP-1 and CCR2, while expression of IL-10 increased. Hepatic expression of CX3CL1, and its receptor, CX3CR1 also increased in STK-/- mice treated with acetaminophen. These data demonstrate that STK plays a role in regulating macrophage recruitment and activation in the liver following acetaminophen administration, and in hepatotoxicity.[Gardner CR et al; Toxicol Appl Pharmacol 262 (2): 139-48 (2012)] Full text: PMC3377817 Abstract: PubMed
        /LABORATORY ANIMALS: Acute Exposure/ Neutrophils and macrophages infiltrate after acetaminophen (APAP)-induced liver injury starts to develop. However, their precise roles still remain elusive. In untreated and control IgG-treated wild-type (WT) mice, intraperitoneal APAP administration (750 mg/kg) caused liver injury including centrilobular hepatic necrosis and infiltration of neutrophils and macrophages, with about 50% mortality within 48 hr after the injection. APAP injection markedly augmented intrahepatic gene expression of inducible nitric oxide synthase (iNOS) and heme oxygenase (HO)-1. Moreover, neutrophils expressed iNOS, which is presumed to be an aggravating molecule for APAP-induced liver injury, while HO-1 was mainly expressed by macrophages. All anti-granulocyte antibody-treated neutropenic WT and most CXC chemokine receptor 2 (CXCR2)-deficient mice survived the same dose of APAP, with reduced neutrophil infiltration and iNOS expression, indicating the pathogenic roles of neutrophils in APAP-induced liver injury. However, APAP caused more exaggerated liver injury in CXCR2-deficient mice with reduced macrophage infiltration and HO-1 gene expression, compared with neutropenic WT mice. An HO-1 inhibitor, tin-protoporphyrin-IX, significantly increased APAP-induced mortality, implicating HO-1 as a protective molecule for APAP-induced liver injury. Thus, CXCR2 may regulate the infiltration of both iNOS-expressing neutrophils and HO-1-expressing macrophages, and the balance between these two molecules may determine the outcome of APAP-induced liver injury. Abstract: PubMed
        Ishida Y et al; Eur J Immunol 36 (4): 1028-38 (2006)
        /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In rats, exposed to dietary doses of 100, 200, 400, 1600 or 3200 mg/kg body weight/day for 13 weeks, deaths occurred at the highest dose. There was evidence of renal toxicity in males of the 1600 mg/kg body weight/day dose group and hepatic and renal toxicity in both sexes at 3200 mg/kg body weight/day. Treatment related increases in liver and kidney weights were seen at all doses. No NOEL could be identified in rats.
        European Medicines Agency (EMA), Committee for Veterinary Medicinal Products: Paracetamol; Summary Report (EMEA/MRL/551/99-FINAL) p.3 (February 1999). Available from, as of March 9, 2014: http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500015516.pdf
        /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In the mouse, after dietary exposure to paracetamol for 13 weeks, at doses of 200, 400, 800, 1600, 3200 and 6400 mg/kg body weight per day hepatotoxicity, organ weight changes and deaths were observed. The NOEL was 400 mg/kg body weight/day in males and 800 mg/kg body weight/day in females.
        European Medicines Agency (EMA), Committee for Veterinary Medicinal Products: Paracetamol; Summary Report (EMEA/MRL/551/99-FINAL) p.2 (February 1999). Available from, as of March 9, 2014: http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500015516.pdf
        /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The aim of the present study was to evaluate the sub-acute oral toxicity of acetaminophen in Sprague Dawley (SD) rats at 250 to 1000 mg/kg body weight /for 28 days/. The following observations were noticed during the study. No mortality in male and female rats, at and up to the dose of 1000 mg/kg body weight (b.wt.). There were abnormal clinical signs observed on female animals at 1000mg/kg b.wt. dose level. There were no difference in body weight gain and no effect on the daily feed consumption. No toxicologically significant effect on the haematological parameters but liver and kidney related biochemical parameter showed significant difference at 1000mg/kg b.wt. in females. No toxicologically significant effect on the urinalysis parameters, absolute and relative organ weights and gross pathological alterations; whereas histopathological alterations were observed in female liver at dose level of 1000mg/kg b.wt. were observed. Based on the findings of this study, the No Observed Adverse Effect Level (NOAEL) of acetaminophen in SD rats, following oral administration at the doses of 250, 500 and 1000 mg/kg on daily basis was found to be 500 mg/kg body weight. Abstract: PubMed
        Venkatesan PS et al; Biol Pharm Bull 37 (7): 1184-90 (2014)
        /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on incr incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3Fl mice that received 600, 3,000, or 6,000 ppm.
        Toxicology & Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 394 (1993) NIH Publication No. 93-2849 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
        /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ High doses of acetaminophen (400 mg/kg) or hydroxyurea (200 mg/kg) given intraperitoneally daily for 5 d caused reduction in relative testicular weight in mice (B6C3/F1/BOM M). Testicular atrophy of several tubules was seen in the hydroxyurea-treated mice 5 d after the last exposure, whereas acetaminophen did not lead to such changes. Exposure to acetaminophen caused neither a depletion of glutathione in the testis nor a marked increase in covalent binding. In contrast, significant decreases in the incorporation of thymidine into the testis were observed during the first 3 hr following a single treatment with acetaminophen (100 to 400 mg/kg) or hydroxyurea (100 to 200 mg/kg). In mice treated with acetaminophen (400 mg/kg) or hydroxyurea (200 mg/kg) daily for 5 d, flow cytometric analysis revealed large reductions in one of the tetraploid populations of testicular cells (mostly early pachytene spermatocytes) on days 5 and 10. Changes in the populations of the various spermatid stages occurred later; thus, both compounds appeared to cause a delay in spermiogenesis. Indications of abnormal chromatin structure were seen in an increased frequency of vas deferens sperm on days 27 and 33 after the last exposure, when measured as increased susceptibility towards DNA denaturation in situ. In conclusion, high doses of acetaminophen or hydroxyurea inhibit DNA synthesis in the testis. The present data indicate that this leads to reduced testicular weight, a reduction in the number of early pachytene spermatocytes, changes in the proportions of the various spermatid stages, and an apparent alteration in sperm chromatin structure. Abstract: PubMed
        Wiger R et al; Reprod Toxicol 9 (1): 21-33 (1995)
        /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Female rats were treated daily with acetaminophen for 2 wk prior to mating at 500 OR 1000 mg/kg. Treatment was continued until day 11.5 after copulation. Fetuses were then analyzed cytogenetically, using a direct method for chromosome prepn. A significant difference in chromosome anomaly was found only between the control group and the 500 mg/kg group. Aneuploidy was the major anomaly observed. Abstract: PubMed
        Tsuruzaki T et al; Nippon Eiseigaku Zasshi 37 (5): 787 (1982)
        /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a reproductive toxicity study, Swiss CD1 mice received paracetamol at doses of 357, 715, 1430 mg/kg body weight. Reductions in fertility and neonatal survival were seen in the F0 generation and decreases in F1 pup weights at 1430 mg/kg body weight. The NOEL for these effects was 715 mg/kg body weight. Sperm abnormalities were also reported at this dose-level, although his was not investigated in the lower dose groups (357 and 715 mg/kg body weight). Hence, no overall NOEL can be identified.
        European Medicines Agency (EMA), Committee for Veterinary Medicinal Products: Paracetamol; Summary Report (EMEA/MRL/551/99-FINAL) p.4 (February 1999). Available from, as of March 9, 2014: http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500015516.pdf
        /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Acetaminophen (paracetamol) is an analgesic-antipyretic drug virtually devoid of typical anti-inflammatory activity and hence free of some of the side-effects of aspirin and related agents (e.g. gastric erosion and bleeding complications). The worldwide use of paracetamol as a household analgesic, including during pregnancy, prompted us to investigate its potentially deleterious effects in that setting. Pregnant rats were treated with paracetamol (150, 500 or 1,500 mg/kg, once a day by gavage) from the first day up to term pregnancy. In the group treated with the lowest doses, no histological changes were noticed in maternal and fetal livers or kidneys when examined under light or electron microscopy. With the higher doses, however, various dose-dependent effects of paracetamol were observed, namely necrotic areas of the liver seen with light microscope and further confirmed by electron microscopy. The kidneys revealed degeneration and necrotic foci under light microscopy with ultrastructural derangements. Electronmicrographs of the liver revealed hepatocytes bearing translucent bodies as a consequence of a dilated smooth endoplasmic reticulum. There were signs of necrosis both in the hepatocytes (lysis of mitochondria and presence of lipid droplets) and renal tissue (mitochondrial cytolysis in convoluted tubules). /The/ data point out the fact that both maternal and fetal tissues can be adversely affected by paracetamol. Abstract: PubMed
        Neto JA et al; Clin Exp Obstet Gynecol 31 (3): 221-4 (2004)
        /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Glutathione (GSH), cysteine, and other low-molecular-weight thiols (LMWT) play a vital role in the detoxication of xenobiotics and endogenous chemicals. Differential alterations of LMWT status in various cell types of the developing embryo may underlie cell-specific sensitivity or resistance to xenobiotics and contribute to embryotoxicity. This study describes the spatial and temporal distribution of LMWTs in rat conceptuses and alterations produced by the non-teratogenic GSH modulator, acetaminophen (APAP). Pregnant female rats were given 125, 250, or 500 mg/kg APAP (po) on gestational day 9. Conceptal LMWT was localized histochemically using mercury orange in cryosections, and GSH and cysteine concentrations were measured by HPLC analysis. Mercury orange histofluorescence revealed a non-uniform distribution of LMWT in untreated conceptal tissues, with strongest staining observed in the ectoplacental cone (EPC), visceral yolk sac (VYS), and embryonic heart. Less intense staining was observed in the neuroepithelium. Following treatment with APAP, tissue-associated LMWT decreased dramatically except in the EPC, while exocoelomic fluid LMWT, and LMWT within embryonic lumens, increased. Exposure to 250 mg/kg APAP decreased embryonic GSH after 6 and 24 h by 46% and 38%, respectively. Acetaminophen (500 mg/kg) decreased embryonic and VYS cysteine content by 54% and 83%, respectively, after 24 hr. Acetaminophen alters the spatial distribution of LMWT in rat conceptuses, particularly with respect to cysteine. The mobilization of cysteine following chemical insult may influence the ability of conceptal cells to maintain normal GSH status due to reduced availability of cysteine for de novo GSH synthesis. Abstract: PubMed
        Beck MJ et al; Toxicol Sci 62 (1): 92-102 (2001)
        /GENOTOXICITY/ Paracetamol was tested for mutagenicity in the Salmonella/mammalian microsome assay. Six testor strains were used (TA1535, TA1537, TA1538, TA100, TA97 and TA98) and experiments were conducted in the presence and absence of a rat liver microsome activation system. Paracetamol did not show any evidence of mutagenic activity at concentrations ranging from 0.1 to 50 mg per plate. Abstract: PubMed
        Jasiewicz ML et al; Mutat Res 190: 95-100 (1987)
        /GENOTOXICITY/ Acetaminophen (APAP) metabolism, cytotoxicity, and genotoxicity were measured in primary cultures of rat hepatocytes. Although 3 mM APAP caused a slight increase in cellular release of lactate dehydrogenase into the culture medium, cellular glutathione concentration (an index of APAP metabolism) was reduced by 50%. APAP at 7 mM was significantly more toxic to these hepatocytes and had a similar but more marked effect on glutathione concentrations. In spite of its cytotoxicity, neither dose of APAP stimulated DNA repair synthesis when monitored by the rate of incorporation of (3)H-thymidine into DNA following exposure to APAP. Thus, although APAP has been shown to be both hepato- and nephrotoxic in several in vivo and in vitro systems, the reactive toxic metabolite of APAP is not genotoxic in rat primary hepatocyte cultures. Abstract: PubMed
        Milam Km, Byard JL; Toxicol Appl Pharmacol 79 (2): 342-7 (1985)
        /GENOTOXICITY/ The genotoxicity of paracetamol, including covalent binding to DNA, induction of DNA single-strand breaks (SSBs), and inhibition of replicative and repair synthesis of DNA, has been investigated in rodents in vivo. In the covalent binding studies male ICR mice were fasted and pretreated with diethyl maleate to deplete hepatic glutathione (GSH) and 300 mg/kg of [G-3H]paracetamol was administered intraperitoneally (i.p.). Animals were killed at 2, 6, 24, 72 and 168 hr after paracetamol and hepatic or renal DNA and protein were isolated and the extent of covalent binding determined. Maximal binding to liver DNA, 8.4 +/- 3.1 pmol/mg of DNA, was observed at 2 hr and declined rapidly to 2.6 pmol/mg at 24 h. Measurable binding (1.4 pmol/mg of DNA) was detected at 7 days. Protein binding in the liver in these animals peaked between 2 and 6 hr (887 pmol/mg of protein at 2 hr) and declined monoexponentially to 52 pmol/mg at 7 days. Although based on a limited body of data, covalent binding was also detected in DNA isolated from the kidney. DNA damage measured as SSBs by alkaline elution was induced in nuclear DNA isolated from the liver but not from the kidney, 2 hr after ip injection of paracetamol at 600 mg/kg in male B6 mice. Only marginal DNA damage was noted at 300 mg/kg. The alkaline elution profile from damaged liver nuclei was markedly biphasic, suggesting that breaks were induced in DNA from a subpopulation of liver cells. The non-hepatotoxic paracetamol regioisomer, acetyl-m-aminophenol (600 mg/kg), which binds covalently to proteins, did not cause DNA SSBs. Abstract: PubMed
        Hongslo JK et al; Mutagenesis 9 (2): 93-100 (1994)
        /ALTERNATIVE and IN VITRO TESTS/ Acetaminophen (APAP) overdose in most species is associated with hepatotoxicity because of the metabolite N-acetyl-p-benzoquinoneimine (NAPQI). In dogs and cats, APAP overdose primarily causes methemoglobinemia and hemolysis. Although NAPQI has been proposed as the responsible intermediate in dogs and cats, it lacks chemical or pharmacokinetic characteristics that favor methemoglobin formation. /The authors/ hypothesized that para-aminophenol (PAP) rather than NAPQI induces methemoglobinemia and that deficient arylamine N-acetyltransferase (NAT) activity in dogs and cats contributes to this species-dependent methemoglobinemia. Erythrocytes from dogs, cats, mice, and rats were exposed in vitro to APAP, NAPQI, and PAP. Only PAP induced methemoglobin and it induced more methemoglobin formation in dog and cat than rat and mouse erythrocytes. PAP also induced more methemoglobin in erythrocytes from Nat1/Nat2 knockout mice than wildtype (WT) mouse erythrocytes (P < 0.05), but less than in dog and cat erythrocytes (P < 0.01). APAP and PAP toxicity were compared in vivo in WT and Nat1/Nat2 knockout mice. APAP caused no hematotoxicity while PAP induced more methemoglobin in NAT1/NAT2 knockout mice than in WT mice (P < 0.05). These results support the hypothesis that PAP is the metabolite responsible for APAP-induced methemoglobinemia and that deficient NAT activity in dogs and cats contributes to this species-dependent toxicity. Abstract: PubMed
        McConkey SE et al; J Vet Pharmacol Ther 32 (6): 585-95 (2009)
        /VETERINARY CASE REPORTS/ Paracetamol, a common human analgesic, is potentially fatal in the cat unless specific therapy is started early. A cat two and one half years old was referred for treatment 14 hr after paracetamol had been administered (173 mg/kg). The cat was moribund and cyanotic and subsequently became anaemic and icteric. Treatment consisted of N-acetylcysteine, ascorbic acid and DL-methionine to decrease toxic effects of the paracetamol and intravenous fluids, blood transfusion and amoxycillin as supportive treatment. The cat recovered clinically during the following 12 days, but some laboratory abnormalities were still present 3 weeks later. Abstract: PubMed
        lkiw JE, Ratcliffe RC; Aust Vet J 64 (8): 245-7 (1987)
        /VETERINARY CASE REPORTS/ An 11-year-old, spayed female Dalmatian was presented with suspected acetaminophen toxicosis. The dog was severely depressed. Methemoglobinemia, facial edema, and hemoglobinuria responded to treatment with intravenous fluids, N-acetylcysteine, ascorbic acid, and sodium bicarbonate. There was no clinical evidence of hepatic damage typical of acetaminophen toxicity in the dog.[MacNaughton SM; Can Vet J 44 (2): 142-4 (2003)] Full text: PMC340050 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Cats are particularly susceptible to paracetamol intoxication because of their imparied glucuronic acid conjugation mechanism and saturation of their sulfate conjugation pathway. ... The clinical signs associated with experimental paracetamol administration to cats included cyanosis followed by anemic, hemoglobinuria, icterus and facial edema in three of four treated cats. ... Paracetamol poisoned cats develop more diffuse liver changes, while hepatic centrilobular lesions are seen in dogs. The abnormal laboratory findings in paracetamol poisoned cats include methemoglobinaemia and an elevated serum alanine aminotransferase activity.
        Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988., p. 91
        /OTHER TOXICITY INFORMATION/ /The purpose of this study was to/ investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice. Using plasma from APAP poisoned mice, either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed, /the researchers/ screened commercially available murine microRNA libraries (SABiosciences, Qiagen Sciences, MD) to evaluate for unique miRNA profiles between these two dosing parameters. /The researchers/ distinguished numerous, unique plasma miRNAs both up- and downregulated in lethally compared to sublethally dosed mice. Of note, many of the greatest up- and downregulated miRNAs, namely 574-5 p, 466 g, 466 f-3p, 375, 29 c, and 148 a, have been shown to be associated with asthma in prior studies. Interestingly, a relationship between APAP and asthma has been previously well described in the literature, with an as yet unknown mechanism of pathology. There was a statistically significant increase in alanine aminotransferase levels in the lethal compared to sublethal APAP dosing groups at the 12 hr time point (P < 0.001). There was 90% mortality in the lethally compared to sublethally dosed mice at the 48 hr time point (P = 0.011). /The researchers/ identified unique plasma miRNAs both up- and downregulated in APAP poisoning which are correlated to asthma development.[Ward J et al; World J Gastroenterol 18 (22): 2798-804 (2012)] Full text: PMC3374983 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. ... A strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions /was presented/. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d x 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, /it was/ demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. ... Results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.[Harrill AH et al; Genome Res 19 (9): 1507-15 (2009)] Full text: PMC2752130 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 hr can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.[Antoine DJ et al; Mol Med 16 (11-12): 479-90 (2010)] Full text: PMC2972397 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Drug-induced liver injury (DILI) is an important cause of acute liver failure with limited therapeutic options. During DILI, oncotic necrosis with concomitant release and recognition of intracellular content amplifies liver inflammation and injury. Amongst these molecules, self-DNA has been widely shown to trigger inflammatory and autoimmune diseases; however, whether DNA released from damaged hepatocytes accumulates into necrotic liver and the impact of its recognition by the immune system remains elusive. Here we showed that treatment with two different hepatotoxic compounds (acetaminophen and thioacetamide) caused DNA release into the hepatocyte cytoplasm, which occurred in parallel with cell death in vitro. Administration of these compounds in vivo caused massive DNA deposition within liver necrotic areas, together with an intravascular DNA coating. Using confocal intravital microscopy, we revealed that liver injury due to acetaminophen overdose led to a directional migration of neutrophils to DNA-rich areas, where they exhibit an active patrolling behavior. DNA removal by intravenous DNASE1 injection or ablation of TLR9-mediated sensing significantly reduced systemic inflammation, liver neutrophil recruitment and hepatotoxicity. Analysis of liver leukocytes by flow cytometry revealed that emigrated neutrophils upregulated TLR9 expression during acetaminophen-mediated necrosis, and these cells sensed and reacted to extracellular DNA by activating the TLR9/NF-?B pathway. Likewise, adoptive transfer of wild-type neutrophils to TLR9-/- mice reversed the hepatoprotective phenotype otherwise observed in TLR9 absence. Conclusion: We described that hepatic DNA accumulation is a novel feature of DILI pathogenesis and blockage of DNA recognition by the innate immune system may consist in a promising therapeutic venue. Abstract: PubMed
        Marques PE et al; Hepatology 61 (1): 348-60 (2015)
        /OTHER TOXICITY INFORMATION/ Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 hr after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP. Abstract: PubMed
        Choi DY et al; Arch Toxicol 89 (2): 211-20 (2015)
        /OTHER TOXICITY INFORMATION/ Autophagy is an evolutionarily conserved biological process that degrades intracellular proteins and organelles including damaged mitochondria through the formation of autophagosome. We have previously demonstrated that pharmacological induction of autophagy by rapamycin protects against acetaminophen (APAP)-induced liver injury in mice. In contrast, in the present study, we found that mice with the liver-specific loss of Atg5, an essential autophagy gene, were resistant to APAP-induced liver injury. Hepatocyte-specific deletion of Atg5 resulted in mild liver injury characterized by increased apoptosis and compensatory hepatocyte proliferation. The lack of autophagy in the Atg5-deficient mouse livers was confirmed by increased p62 protein levels and the absence of LC3-lipidation as well as autophagosome formation. Analysis of histological and clinical chemistry parameters indicated that the Atg5 liver-specific knockout mice are resistant to APAP overdose (500 mg/kg). Further investigations revealed that the bioactivation of APAP is normal in Atg5 liver-specific knockout mice although they had lower CYP2E1 expression. There was an increased basal hepatic glutathione (GSH) content and a faster recovery of GSH after APAP treatment due to persistent activation of Nrf2, a transcriptional factor regulating drug detoxification and GSH synthesis gene expression. In addition, we found significantly higher hepatocyte proliferation in the livers of Atg5 liver-specific knockout mice. Taken together, our data suggest that persistent activation of Nrf2 and increased hepatocyte proliferation protect against APAP-induced liver injury in Atg5 liver-specific knockout mice.[Ni HM et al; Toxicol Sci 127 (2): 438-50 (2012)] Full text: PMC3355320 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3 ug. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200 ug produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5 ug. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen. Abstract: PubMed
        Liu J et al; Neurosci Lett 536: 64-8 (2013)
        /OTHER TOXICITY INFORMATION/ Acetaminophen (APAP) overdose is a major cause of acute liver failure. The glutathione (GSH) precursor N-acetylcysteine (NAC) is used to treat patients with APAP overdose for up to 48 hours. Although it is well established that early treatment with NAC can improve the scavenging of the reactive metabolite N-acetyl-p-benzoquinone imine, protective mechanisms at later times remain unclear. To address this issue, fasted C3Heb/FeJ mice were treated with 300 mg/kg APAP and then received intravenously 0.65 mmol/kg GSH or NAC at 1.5 hours after APAP. The animals were sacrificed at 6 hours. APAP alone caused severe liver injury with peroxynitrite formation and DNA fragmentation, all of which was attenuated by both treatments. However, GSH (-82%) was more effective than NAC (-46%) in preventing liver injury. Using nuclear magnetic resonance spectroscopy to measure tissue adenosine triphosphate (ATP) levels and the substrate flux through the mitochondrial Krebs cycle, it was observed that the reduced liver injury correlated with accelerated recovery of mitochondrial GSH content, maintenance of ATP levels, and an increased substrate supply for the mitochondrial Krebs cycle compared with APAP alone. NAC treatment was less effective in recovering ATP and mitochondrial GSH levels and showed reduced substrate flux through the Krebs cycle compared with GSH. However, increasing the dose of NAC improved the protective effect similar to GSH, suggesting that the amino acids not used for GSH synthesis were used as mitochondrial energy substrates. Delayed treatment with GSH and NAC protect against APAP overdose by dual mechanisms-that is, by enhancing hepatic and mitochondrial GSH levels (scavenging of reactive oxygen and peroxynitrite)-and by supporting the mitochondrial energy metabolism.[Saito C et al; Hepatology 51 (1): 246-54 (2010)] Full text: PMC2977522 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca(2+) homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca(2+) concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca(2+) rise. Here we report that the channel responsible for Ca(2+) entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.[Kheradpezhouh E et al; Proc Natl Acad Sci U S A 111 (8): 3176-81 (2014)] Full text: PMC3939869 Abstract: PubMed
        /OTHER TOXICITY INFORMATION/ Acetaminophen (APAP) is safe at therapeutic dosage but can cause severe hepatotoxicity if used at overdose. The mechanisms of injury are not yet fully understood, but previous reports had suggested that the mitochondrial permeability transition (mPT) may be involved in triggering hepatocellular necrosis. We aimed at inhibiting mitochondrial cyclophilin D (CypD), a key regulator of the mPT, as a potential therapeutic target in APAP hepatotoxicity. Wildtype mice treated with a high dose of APAP (600 mg/kg, intraperitoneal) developed typical centrilobular necrosis, which could not, however, be prevented by cotreatment with the selective CypD inhibitor, Debio 025 (alisporivir, DEB025, a nonimmunosuppressive cyclosporin A analog). Similarly, genetic ablation of mitochondrial CypD in Ppif-null mice did not afford protection from APAP hepatotoxicity. To determine whether APAP-induced peroxynitrite stress might directly activate mitochondrial permeabilization, independently of the CypD-regulated mPT, we coadministered the peroxynitrite decomposition catalyst Fe-TMPyP (10 mg/kg, intraperitoneal, 90 minutes prior to APAP) to CypD-deficient mice. Liver injury was greatly attenuated by Fe-TMPyP pretreatment, and mitochondrial 3-nitrotyrosine adduct levels (peroxynitrite marker) were decreased. Acetaminophen treatment increased both the cytosolic and mitochondria-associated P-JNK levels, but the c-jun-N-terminal kinase (JNK) signaling inhibitor SP600125 was hepatoprotective in wildtype mice only, indicating that the JNK pathway may not be critically involved in the absence of CypD. Conclusion: These data support the concept that an overdose of APAP results in liver injury that is refractory to pharmacological inhibition or genetic depletion of CypD and that peroxynitrite-mediated cell injury predominates in the absence of CypD. Abstract: PubMed
        LoGuidice A, Boelsterli UA; Hepatology 54 (3):969-78 (2011)
        /OTHER TOXICITY INFORMATION/ Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.[McGill MR et al; J Clin Invest 122 (4): 1574-83 (2012)] Full text: PMC3314460 Abstract: PubMed

      11. Human Toxicity Values

        In adults, hepatic toxicity rarely has occurred with acute overdoses of less than 10 g, although hepatotoxicity has been reported in fasting patients ingesting 4-10 g of acetaminophen. Fatalities are rare with less than 15 g.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2210

      12. Non-Human Toxicity Values

        LD50 Rat oral 2400 mg/kg
        Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
        LD50 Rat ip 1205 mg/kg
        Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
        LD50 Mouse oral 338 mg/kg
        Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
        LD50 Mouse ip 367 mg/kg
        Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994
        LD50 Mouse sc 310 mg/kg
        Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1994

      13. Ecotoxicity Values

        LC50; Species: Anas platyrhynchos (Mallard duck) age 9 days; diet >5900 ppm for 8 days
        USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Colinus virginianus (Northern Bobwhite Quail) age 14 days; diet >5900 ppm for 8 days
        USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LD50; Species: Colinus virginianus (Northern Bobwhite Quail) age 22 weeks; oral via capsule >2250 mg/kg
        USEPA, Office of Pesticide Programs; Pesticide Ecotoxicity Database (2000) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        EC50; Species: Xenopus laevis (African clawed toad) Blastula; Conditions: freshwater, renewal, 23 deg C; Concentration: >100000 ug/L for 96 hr; Effect: increased developmental deformation /99.1% purity/
        Richards SM, Cole SE; Ecotoxicology 15 (8): 647-656 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        EC50; Species: Xenopus laevis (African clawed toad) embryo; Conditions: freshwater, renewal, 23 deg C, FETAX solution, unactivated; Concentration: 143300 ug/L for 96 hr (95% confidence interval: 132900-154600 ug/L); Effect: increased abnormal development (gut miscoiling, craniofacial defects, abnormal mouth development, muscular kinking, heart maldevelopment, pericardial and ophthalmic edema /formulated product/
        Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        EC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 deg C, FETAX solution, activated with Aroclor 1254-induced rat liver microsomes; Concentration: 20100 ug/L for 96 hr (95% confidence interval: 8900-45800 ug/L); Effect: increased abnormal development (gut miscoiling, hypognathia, lateral body flexure, skeletal kinking, microencephaly /formulated product/
        Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 deg C, FETAX solution, unactivated; Concentration: 191100 ug/L for 96 hr (95% confidence interval: 168500-216700 ug/L) /formulated product/
        Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Xenopus laevis (African clawed frog) embryo; Conditions: freshwater, renewal, 23 deg C, FETAX solution, activated with Aroclor 1254-induced rat liver microsomes; Concentration: 49600 ug/L for 96 hr (95% confidence interval: 45500-54200 ug/L) /formulated product/
        Fort DJ et al; Drug Chem Toxicol (NY) 15 (4): 329-350 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Artemia salina (Brine Shrimp) age 2-3 instar larva; Conditions: saltwater, static; Concentration: 3820 umol/L for 24 hr /formulated product/
        Calleja MC, Persoone G; ATLA Altern Lab Anim 20: 396-405 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Streptocephalus proboscideus (Fairy Shrimp) age 2-3 instar larva; Conditions: freshwater, static, 25 deg C; Concentration: 196 umol/L for 24 hr /formulated product/
        Calleja MC, Persoone G; ATLA Altern Lab Anim 20: 396-405 (1992) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        EC50; Species: Daphnia magna (Water Flea) age 6-24 hr; Conditions: freshwater, static, 20 deg C, pH > or =7.0; Concentration: 13000 ug/L for 24 hr (95% confidence interval: 6000-32000 ug/L); Effect: intoxication, immobilization /formulated product/
        Kuhn R et al; Water Res 23 (4): 495-499 (1989) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        EC50; Species: Daphnia magna (Water Flea) age 6-24 hr; Conditions: freshwater, static, 20 deg C, pH > or =7.0; Concentration: 9200 ug/L for 48 hr (95% confidence interval: 6100-14000 ug/L); Effect: intoxication, immobilization /formulated product/
        Kuhn R et al; Water Res 23 (4): 495-499 (1989) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 20 deg C; Concentration: >32 ug/L for 48 hr /98-101% purity/
        Brun GL et al; Environ Toxicol Chem 25 (8): 2163-2176 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 25 deg C, pH 7.8, hardness 170 mg/L CaCO3, alkalinity 110 mg/L CaCO3; Concentration: 20100 ug/L for 48 hr /formulated product/
        Han GH et al; Environ Toxicol Chem 25 (1): 265-271 (2006) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Oryzias latipes (Japanese Medaka) length 2.0 cm; Conditions: freshwater, renewal, 25 deg C, dissolved oxygen >80% saturated; Concentration: >160000 ug/L for 48 hr /formulated product/
        Kim Y et al; Environ Int 33 (3): 370-375 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Oryzias latipes (Japanese Medaka) length 2.0 cm; Conditions: freshwater, renewal, 25 deg C, dissolved oxygen >80% saturated; Concentration: >160000 ug/L for 96 hr /formulated product/
        Kim Y et al; Environ Int 33 (3): 370-375 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm
        LC50; Species: Pimephales promelas (Fathead minnow) age 33 days, length 24.6 mm, weight 0.246 g; Conditions: flow through, 24.7 deg C, dissolved oxygen 5.9 mg/L, hardness 51.0 mg/L CaCO3, alkalinity 45.0 mg/L CaCO3, pH 7.4; Concentration: 814 mg/L for 96 hr /99% purity/
        Brooke, L.T., D.J. Call, D.T. Geiger and C.E. Northcott (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Superior, WI: Center for Lake Superior Environmental Studies Univ. of Wisconsin Superior, 1984., p. 291
        EC50; Species: Lemna minor (Duckweed) age 3-4 fronds; Conditions: freshwater, pH 5.5-8.0; Concentration: >200000 ug/L for 168 hr /formulated product/
        Kaza M et al; Fresenius Environ Bull 16 (5): 524-531 (2007) as cited in the ECOTOX database. Available from, as of January 16, 2014: http://cfpub.epa.gov/ecotox/quick_query.htm

      14. National Toxicology Program Reports

        14-DAY STUDIES. Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES. Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male. GENETIC TOXICOLOGY. Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9. CONCLUSIONS Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice.
        Toxicology & Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 394 (1993) NIH Publication No. 93-2849 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
        Acetaminophen (ACET) ... was tested for its effects on reproduction & fertility in CD-1 mice, following the RACB protocol. Data on body weights, clinical signs, & food & water consumption from a 2 wk dose-range-finding study (Task 1) were used to set exposure levels for the Task 2 continuous cohabitation phase at 0.25%, 0.5%, & 1.0% in the diet. Feed consumption was reduced only in females at the top dose level, by 10-20%. Measured body weight & feed consumption allowed exposure to be estimated as nearly equal to 370, 770, & 1400 mg/kg/day. During Task 2, 4 animals died: 2, 1, & 1 each in the low, middle, & high dose groups. During Task 2, the number of litters/pair decreased by 3% for the high dose group. No changes were noted in the number of pups/litter, viability, or in adjusted pup weight. The slight reduction in number of litters/pair was judged to be too small to yield a detectable change during the statistically-less-powerful Task 3 crossover mating, so no crossover test was conducted. For the F1 evaluation, the last litter in Task 2 from all dose groups was nursed to weaning, & reared on the diet consumed by their parents. F1 pup body weights were reduced at all doses for both sexes by nearly equal to 6-18%. Pup body weight gain to weaning was also reduced for the medium & high dose males (17% & 34%), & for females at all doses (10-28%). All dose groups were reared consuming the same diet provided to their parents. The body weight differences that were seen during nursing were reduced, but still present, at the time of mating. At the F1 mating, the F2 pup weight adjusted for litter size was decreased by 11% at the high dose level. No other reproductive endpoints were affected. After the F2 pups were delivered & evaluated, the F1 adults from only the control & high dose groups were killed & necropsied. Compared to controls, the high dose males weighed 10% less, while organ weights were not affected. Sperm abnormalities increased from 7% (controls) to 16% at the high dose. High dose females weighed 8% less, while adjusted liver weight was increased by 10%. In summary, the greatest toxicity produced by acetaminophen in the diet of Swiss mice was on the growing neonate (reduced weight gain during nursing). Fertility endpoints (ability to bear normal numbers of normal-weight young) were generally not affected.
        Department of Health & Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Acetaminophen : (CAS # 103-90-2): Reproduction and Fertility Assessment in CD-1 Mice When Administered in the Feed, NTP Study No. RACB83079 (November 21, 1984) Available from, as of August 15, 2002: http://ntp.niehs.nih.gov/index.cfm?objectid=0847F35A-0850-D1E7-B02ED4DDD150F990

      15. Populations at Special Risk

        Acetaminophen is contraindicated: in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation and in patients with severe hepatic impairment or severe active liver disease.
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7
        Because there is some evidence that chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, chronic alcoholics should be cautioned to avoid regular or excessive use of acetaminophen, or alternatively, to avoid chronic ingestion of alcohol.
        American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2209
        Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children, /the researchers/ studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. To ascertain outcome information /the researchers/ used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. /The researchers/ estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < 0.001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders /the researchers/ evaluated. Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed. Abstract: PubMed
        Liew Z et al; JAMA Pediatr 168 (4):313-20 (2014)
        Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance = 30 mL/min).
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7

      16. Protein Binding

        25%

    2. Ecological Information

      1. EPA Ecotoxicity

        1 to 3 of 3
        Record IDPesticide TypeOrganismDose TypeToxicity
        26862Special UseBobwhite quailLD50> 2250 MGK
        26863Special UseMallard duckLC50> 5900 PPM
        26900Special UseBobwhite quailLC50> 5900 PPM

      2. ICSC Environmental Data

        The substance is toxic to aquatic organisms. It is strongly advised not to let the chemical enter into the environment.

      3. Environmental Fate/Exposure Summary

        Acetaminophen's production and use as an analgesic and the production and use in the manufacture of azo dyes and photographic chemicals may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.3X10-5 mm Hg at 25 deg C indicates acetaminophen will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase acetaminophen will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 22 hrs. Particulate-phase acetaminophen will be removed from the atmosphere by wet and dry deposition. Acetaminophen absorbs light at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, acetaminophen is expected to have very high mobility based upon an estimated Koc of 21. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 8.8X10-10 atm-cu m/mole. Acetaminophen is not expected to volatilize from dry soil surfaces based upon its vapor pressure. The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days, respectively, suggesting that biodegradation may be an important environmental fate process in soil and water. If released into water, acetaminophen is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to acetaminophen may occur through inhalation and dermal contact with this compound at workplaces where acetaminophen is produced or used. Monitoring and use data indicate that the general population may be exposed to acetaminophen via ingestion of drinking water, and ingestion and dermal contact with this compound and other products containing acetaminophen. Exposure to acetaminophen among the general population may be widespread through use of the drug as an analgesic. (SRC)

      4. Artificial Sources

        Acetaminophen's administration and use as an analgesic and production and use in the manufacture of azo dyes and photographic chemicals(1) may result in its release to the environment through various waste streams(SRC).
        (1) O'Neil MJ, ed; The Merck index. 15th ed. Whitehouse Station, NJ: Merck & Co., p 11 (2013)

      5. Environmental Fate

        TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 21(SRC), determined from a log Kow of 0.46(2) and a regression-derived equation(3), indicates that acetaminophen is expected to have very high mobility in soil(SRC). Volatilization of acetaminophen from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 8.9X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.29X10-5 mm Hg(4), and water solubility, 1.4X10+4 mg/L(5). Acetaminophen is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days(6), respectively, suggesting that biodegradation may be an important environmental fate process in soil given acclimation(SRC).
        (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, (1989) (5) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed. Boca Raton, FL: CRC Press p. 492 (2010) (6) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985)
        AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 21(SRC), determined from a log Kow of 0.46(2) and a regression-derived equation(3), indicates that acetaminophen is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 8.9X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 6.29X10-5 mm Hg(5), and water solubility, 1.4X10+4 mg/L(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). The biodegradation half-lives for non-adapted, phenol-adapted, and cresol-adapted activated sludge were 21, 40, and 13 days(8), respectively, suggesting that biodegradation may be an important environmental fate process in water given acclimation(SRC).
        (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, (1989) (6) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed. Boca Raton, FL: CRC Press p. 492 (2010) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985)
        ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acetaminophen, which has an estimated vapor pressure of 6.3X10-5 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase acetaminophen is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hrs(SRC), calculated from its rate constant of 1.8X10-11 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(3). Particulate-phase acetaminophen may be removed from the air by wet and dry deposition(SRC). Acetaminophen absorbs light at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
        (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) NIST; NIST Chemistry WebBook. Acetaminophen (103-90-2). NIST Standard Reference Database No. 69, June 2005 Release. Washington, DC: US Sec Commerce. Available from, as of Mar 6, 2014: http://webbook.nist.gov

      6. Biodegredation

        AEROBIC: Acetaminophen has been categorized as readily biodegradable following acclimation(1). A half-life of 20 days has been reported for acetaminophen using an activated sludge inoculum(2). Half-lives of 40 and 17 days were observed when using activated sludge inoculums acclimated to phenol(3) and cresol(4), respectively. Acetaminophen reached 94% of its theoretical BOD in 6 days using an activated sludge inoculum and the Zahn-Wellens test(5). The rate constants for non-adapted, phenol-adapted, and cresol-adapted activated sludge (sludge concentrations of 500, 10, and 50 mg/L) were 0.141X10-2, 0.713X10-3, and 0.215X10-2 1/hr, respectively(6); half-lives are 21, 40, and 13 days, respectively(SRC). Acetaminophen, present at 100 ug/L, exhibited biodegradation rates of 0.014/hr and 0.00051/hr in 5 days using Tamlya and Tsumeta River water (Japan), respectively, and the OECD 301-A river die-away test. The corresponding half-lives are 50 and 1400 hours, respectively(7).
        (1) Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) (2) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 37-56 (1983) (3) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 49-54 (1983) (4) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 13: 59-65 (1984) (5) Wellens H; Z Wasser Abwasser Forsch 23: 85-98 (1990) (6) Yonezawa Y et al; Kogai Shigen Kenkyusho Iho 15: 75-86 (1985) (7) Yamamoto H et al; Water Res 43: 351-362 (2009)
        AEROBIC: Occurrence and removal efficiencies of fifteen pharmaceuticals were investigated in a conventional municipal wastewater treatment plant in Michigan. Concentrations of these pharmaceuticals were determined in both wastewater and sludge phases by a high-performance liquid chromatograph coupled to a tandem mass spectrometer. Detailed mass balance analysis was conducted during the whole treatment process to evaluate the contributing processes for pharmaceutical removal. Among the pharmaceuticals studied, demeclocycline, sulfamerazine, erythromycin and tylosin were not detected in the wastewater treatment plant influent. Other target pharmaceuticals detected in wastewater were also found in the corresponding sludge phase. The removal efficiencies of chlortetracycline, tetracycline, sulfamerazine, acetaminophen and caffeine were >99%, while doxycycline, oxytetracycline, sulfadiazine and lincomycin exhibited relatively lower removal efficiencies (e.g., <50%). For sulfamethoxazole, the removal efficiency was approximately 90%. Carbamazepine manifested a net increase of mass, i.e. 41% more than the input from the influent. Based on the mass balance analysis, biotransformation is believed to be the predominant process responsible for the removal of pharmaceuticals (22% to 99%), whereas contribution of sorption to sludge was relatively insignificant (7%) for the investigated pharmaceuticals. Abstract: PubMed
        Gao P et al; Chemosphere 88(1):17-24 (2012)
        ANAEROBIC: Acetaminophen, present at 50 ppm carbon, reached 93% of its theoretical methane production in 56 days using a digestor sludge inoculum fortified with mineral salts(1). A 30-75% theoretical methane production resulted when using inoculum from a secondary digestor(1).[(1) Shelton DR, Tiedje JM; Appl Environ Microbiol 47: 449-69 (1984)] Full text: PMC239700 Abstract: PubMed

      7. Abiotic Degredation

        The rate constant for the vapor-phase reaction of acetaminophen with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Acetaminophen is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Acetaminophen absorbs at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). Acetaminophen, present at 100 ug/L in 30-mL quartz test tubes and exposed to direct sunlight, exhibited half-lives of 56 and 35 hours in August 2006 and May 2007, respectively(4). Acetaminophen was present in a mixture of eight pharmaceuticals which were added to aquatic outdoor field microcosms at low, medium, high, and ultra-high concentrations (acetaminophen concentrations of 0.83, 33.98, 132.00 and 2,190 ug/L, respectively)(5). Half-lives in the field were 1, 0.9, 0.7. and 1.1 days, respectively. Lab results suggest that neither hydrolysis nor biodegradation were important environmental fate processes. However, photodegradation did play an important role in limiting the presence of the test compounds(4). Loss due to indirect photolysis reactions involving the OH radical was 100% in 15 days with no loss observed in controls(5,6).
        (1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) NIST; NIST Chemistry WebBook. CHEMICAL (103-90-2). NIST Standard Reference Database No. 69, June 2005 Release. Washington, DC: US Sec Commerce. Available from, as of Mar 6, 2014: http://webbook.nist.gov (4) Yamamoto H et al; Water Res 43: 351-362 (2009) (5) Lam MW et al; Environ Sci Toxicol 37: 899-907 (2003) (6) Lam MW et al; Environ Toxicol Chem 23: 1431-40 (2004)
        88% Transformation of 10 umol/L acetaminophen in pure water at neutral pH using 57 umol/L hypochlorite (4 ppm as Cl2) was observed in a test designed to simulate chlorination carried out over time to simulate wastewater disinfection. This treatment produced 11 discernable products, including the toxic compounds 1,4-benzoquinone and N-acetyl-p-benzoquinone imine, 25% and 1.5% of the initial acetaminophen concentration, respectively, in 1 hour reaction time(1).
        (1) Bender M, Maccrehan WA; Environ Sci Technol 40: 516-522 (2006)

      8. Bioconcentration

        An estimated BCF of 3 was calculated in fish for acetaminophen(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
        (1) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/ (3) Franke C et al; Chemosphere 29: 1501-14 (1994)

      9. Soil Adsorption/Mobility

        The Koc of acetaminophen is estimated as 21(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that acetaminophen is expected to have very high mobility in soil. The pKa of acetaminophen is 9.38(4), indicating that this compound will exist partially in the anion form in the environment and anions generally adsorb less strongly to soils containing organic carbon and clay than their neutral counterparts(5). However, low mobilty was observed in soils with a high organic content. Kd values of 46 and 36 in clayey silt and silty sand, respectively, have been reported when the test compound was applied in standard dilution(6). Kd values of 45 and 41 in clayey silt and silty sand, respectively, have been reported when acetaminophen was applied as a test sludge; the average Kd value of 42 indicated low mobility(6). Acetaminophen, present at <0.009 ug/L, was not detected in leachate water (treated effluent from a muncipal wastewater treatment facility) following a 23-day soil column leaching experiment using Mohall-Laveen sandy loam (detection limit = 0.009 ug/L)(7).
        (1) Sangster J; LOGKOW Database. A databank of evaluated octanol-water partition coefficients (Log P). Available from, as of Mar 6, 2014: http://logkow.cisti.nrc.ca/logkow/search.html (2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Mar 6, 2014: http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Dastmalchi S et al; J Sch Pharm., Med Sci Univ Tehran 4: 7-14 (1995) (5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000) (6) Kreuzig R et al; Fresnius Environ Bull 12: 550-8 (2003) (7) Cordy GE et al; Ground Water Monit Remed 24: 58-69 (2004)

      10. Volatilization from Water/Soil

        The Henry's Law constant for acetaminophen is estimated as 8.9X10-10 atm-cu m/mole(SRC) derived from its vapor pressure, 6.29X10-5 mm Hg(1), and water solubility, 1.4X10+4 mg/L(2). This Henry's Law constant indicates that acetaminophen is expected to be essentially nonvolatile from water and moist soil surfaces(3). Acetaminophen is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).
        (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, (1989) (2) Yalkowsky SH et al; Handbook of Aqueous Solubility Data. 2nd ed. Boca Raton, FL: CRC Press p. 492 (2010) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)

      11. Water Concentrations

        GROUNDWATER: Acetaminophen (reporting limit 0.009 ug/L) was not detected in the leachate plume down gradient of the Norman municipal landfill in central Oklahoma, sampled Sept 6, 2000(1).
        (1) Barnes KK et al; Ground Water Monit Remed 24: 119-26 (2004)
        GROUNDWATER: Dewatered municipal biosolids (DMBs) were applied to a field at a rate of approximately 22 Mg dw/ha in Oct 2008. Pharmaceuticals and personal care products (PPCPs) were monitored in groundwater, tile drainage, soil, DMB aggregates incorporated into the soil post-land application, and in the grain of wheat grown on the field for a period a about 1 year following application. Over 80 PPCPs were analyzed in the source DMB. PPCPs selected for indpeth monitoring included: antibiotics (tetracyclines, fluoroquinolones), bacteriocides (triclosan, triclocarban), beta-blockers (atenolol, propranolol, metaprolol), antidepressants (flouxetine, citalopram, venlafaxine, sertraline), antifungals (miconazole), analgesics (acetaminophen, ibuprofen) and antiiconvulsants (carbamazepine). PPCPs in tile were observed twice, approximately 3 weeks and 2 months post-application. Of all PPCPs measured in tile drainage, only carbamazepine, ibuprofen, acetaminophen, triclosan, triclocarban, venlafaxine, and citalopram were detected (5-74 ng/L). PPCPs were not detected in groundwater >2 m depth below the soil surface, and concentrations above detection limits at 2 m depth were only observed once just after the first rain event post-application. In groundwater, all compounds in tile, except carbamazepine, acetaminophen and citalopram, were detected (10-10 ng/L). PPCPs were detected in DMB aggregates incorporates in soil up to 1 year post-application, with miconazole and fluoxetine having the lowest percent reductions over 1 year (approximately 50%). For several compounds in these aggregates, concentration declines were of exponential decay form. No PPCPs were detected in the grain of wheat planted post-application on the field. No PPCPs were ever detected in water, soil or grain samples from the reference plot, where no DMB was applied. Abstract: PubMed
        Gottschall N et al; Chemosphere 87(2): 194-203 (2012)
        DRINKING WATER: Acetaminophen was detected in samples from Jefferson Parish East Bank drinking water plant, New Orleans, Louisiana at concentrations of 0.2, not detected to 0.2, and not detected to 0.1 ng/L from the Mississippi River, precipitator, and finished water, respectively, sampled from September - November, 2001(1). A drinking water treatment plant in Windsor, Ontario, Canada had a concentration of 0.2 ng/L in finished water(1). Abstract: PubMed
        (1) Boyd GR et al; Sci Total Environ 311: 135-49 (2003)
        SURFACE WATER: Acetaminophen was not detected in samples from Lake Pontchartrain nor the Mississippi River at the Bonnet Carrie Spillway, New Orleans, Louisiana (detection limit 45 ng/L), sampled from September - November, 2001(1). It was not detected in intake water from the Detroit River to a drinking water treatment plant in Windsor, Ontario, Canada(1). As part of a National Reconnaissance of 139 US streams across 30 state conducted from 1999 through 2000, acetaminophen concentration was detected in 23.8% of 84 samples, maximum and median concentrations of 10 and 0.11 ug/L, respectively, reporting limit 0.009 ug/L(2). Acetaminophen was tested for in 23 stream locations of 10 Iowa cities; high flow sample maximum concentration was 0.059 ug/L, 43.5% frequency, not detected during normal-flow concentrations, and maximum low-flow concentration was 1.95 ug/L and 20.0% frequency(3). Acetaminophen exhibited a 0% frequency of detection in 7 surface water samples from the Great Lakes, detection limit 0.0045 ug/L(4). The compound was present at 10.1 ng/L in samples from Dutch Coast of the North Sea, collected from 1996 to 2005(5).
        (1) Boyd GR et al; Sci Total Environ 311: 135-49 (2003) (2) Kolpin DW et al; Environ Sci Technol 36: 1202-11 (2002) (3) Kolpin DW et al; Sci Total Environ 348: 119-30 (2004) (4) Klecka G et al; Rev Environ Contam Toxicol 207: 1-93 (2010) (5) Walraven N, Laane RWPM; Rev Environ Contam Toxicol 199: 1-18 (2008)

      12. Effluents Concentrations

        Acetaminophen was detected, not quantified in four of eight secondary effluents from publicly-owned treatment works in Illinois, sampled from February to June, 1980(1). It was not detected in effluent from an industrial plant sampled as part of this same study(1). Acetaminophen was detected in sewage treatment plant effluent from Louisiana at concentrations of 1.1 and 1.2 ng/L, sampled from September - November, 2001(2). It was not detected in effluent from a pilot plant in Windsor, Ontario, Canada(2).
        (1) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (2) Boyd GR et al; Sci Total Environ 311: 135-49 (2003)

      13. Milk Concentrations

        EXPERIMENTAL: In 12 nursing mothers (nursing 2-22 months) given a single oral dose of 650 mg, peak levels of acetaminophen occurred at 1-2 hours in the range of 10-15 ug/mL. Assuming 90 mL of milk were ingested at 3-, 6-, and 9-hour intervals after ingestion, the amount of drug available to the infant was estimated to range from 0.04% to 0.23% of the maternal dose.
        Briggs, G.G., Freeman, R.K., Yaffee, S.J.; Drugs in Pregancy and Lactation Nineth Edition. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA. 2011, p. 11
        EXPERIMENTAL: While studies with Ofirmev have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration. Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 - 2% of the maternal dose. There is one well-documented report of a rash in a breast-fed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Caution should be exercised when Ofirmev is administered to a nursing woman.
        US Natl Inst Health; DailyMed. Current Medication Information for OFIRMEV (acetaminophen) injection, solution (October 2013). Available from, as of March 6, 2014: ttp://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7

      14. Probable Routes of Human Exposure

        According to the 2006 TSCA Inventory Update Reporting data, the number of persons reasonably likely to be exposed in the industrial manufacturing, processing, and use of acetaminophen is 1 to 99; the data may be greatly underestimated(1).
        (1) US EPA; Inventory Update Reporting (IUR). Non-confidential 2006 IUR Records by Chemical, including Manufacturing, Processing and Use Information. Washington, DC: U.S. Environmental Protection Agency. Available from, as of Mar 6, 2014: http://cfpub.epa.gov/iursearch/index.cfm
        NIOSH (NOES Survey 1981-1983) has statistically estimated that 65,107 workers (56,260 of these were female) were potentially exposed to acetaminophen in the US(1). Occupational exposure to acetaminophen may occur through inhalation and dermal contact with this compound at workplaces where acetaminophen is produced or used(SRC). Monitoring and use data indicate that the general population may be exposed to acetaminophen via ingestion of drinking water, and ingestion and dermal contact with this compound and other products containing acetaminophen(SRC). Exposure to acetaminophen among the general population may be widespread through use of the drug as an analgesic(SRC).
        (1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Mar 6, 2014: http://www.cdc.gov/noes/

  13. Literature

    1. Depositor Provided PubMed Citations

    2. NLM Curated PubMed Citations

    3. Synthesis References

      Jeffrey L. Finnan, Rudolph E. Lisa, Douglass N. Schmidt, "Process for preparing spray dried acetaminophen powder and the powder prepared thereby." U.S. Patent US4710519, issued October, 1975.

    4. General References

      1. Kis B, Snipes JA, Busija DW: Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther. 2005 Oct;315(1):1-7. Epub 2005 May 6. Pubmed
      2. Aronoff DM, Oates JA, Boutaud O: New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006 Jan;79(1):9-19. Pubmed
      3. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S: Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006 Fall-Winter;12(3-4):250-75. Pubmed
      4. Graham GG, Scott KF: Mechanism of action of paracetamol. Am J Ther. 2005 Jan-Feb;12(1):46-55. Pubmed
      5. Ohki S, Ogino N, Yamamoto S, Hayaishi O: Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem. 1979 Feb 10;254(3):829-36. Pubmed
      6. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S: Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006 Fall-Winter;12(3-4):250-75. Pubmed
      7. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31. Epub 2002 Sep 19. Pubmed
      8. Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder JS: Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects. Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):155-65. doi: 10.1002/bdra.20535. Pubmed
      9. Hazai E, Vereczkey L, Monostory K: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun. 2002 Mar 8;291(4):1089-94. Pubmed

    5. Metabolite References

      1 to 5 of 19
      View More
      PMIDReference
      1732127de Morais SM, Uetrecht JP, Wells PG: Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992 Feb;102(2):577-86.
      11901099Muldrew KL, James LP, Coop L, McCullough SS, Hendrickson HP, Hinson JA, Mayeux PR: Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. Drug Metab Dispos. 2002 Apr;30(4):446-51.
      3987005Bales JR, Nicholson JK, Sadler PJ: Two-dimensional proton nuclear magnetic resonance "maps" of acetaminophen metabolites in human urine. Clin Chem. 1985 May;31(5):757-62.
      12845506van der Marel CD, Anderson BJ, Pluim MA, de Jong TH, Gonzalez A, Tibboel D: Acetaminophen in cerebrospinal fluid in children. Eur J Clin Pharmacol. 2003 Aug;59(4):297-302. Epub 2003 Jul 4.
      6644552Watari N, Iwai M, Kaneniwa N: Pharmacokinetic study of the fate of acetaminophen and its conjugates in rats. J Pharmacokinet Biopharm. 1983 Jun;11(3):245-72.

  14. Patents

    RE39221

    1. Depositor-Supplied Patent Identifiers

    2. FDA Orange Book Patents

      FDA Orange Book Patents: 1 of 16
      Patent5972916
      ExpirationJul 14, 2017
      ApplicantGLAXOSMITHKLINE CONS
      Drug ApplicationN020802 (Over-the-Counter Drug: EXCEDRIN (MIGRAINE). Ingredients: ACETAMINOPHEN; ASPIRIN; CAFFEINE)
      FDA Orange Book Patents: 2 of 16
      Patent6028222
      ExpirationAug 5, 2017. 6028222*PED expiration date: Feb 5, 2018
      ApplicantMALLINCKRODT IP
      Drug ApplicationN022450 (Prescription Drug: OFIRMEV. Ingredients: ACETAMINOPHEN)
      FDA Orange Book Patents: 3 of 16
      Patent6992218
      ExpirationJun 6, 2021. 6992218*PED expiration date: Dec 6, 2021
      ApplicantMALLINCKRODT IP
      Drug ApplicationN022450 (Prescription Drug: OFIRMEV. Ingredients: ACETAMINOPHEN)
      View All 16 FDA Orange Book Patents

  15. Biomolecular Interactions and Pathways

    1. Protein Bound 3-D Structures

    2. Biosystems and Pathways

    3. DrugBank Interactions

      DrugBank Interactions: 1 of 23
      TargetProstaglandin G/H synthase 2
      Actioninhibitor
      General FunctionProstaglandin-endoperoxide synthase activity
      Specific FunctionConverts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and brain, and in pathological conditions, such as in cancer. PTGS2 is responsible for production of inflammatory prostaglandins. Up-regulation of PTGS2 is also associated with increased cell adhesion, phenotypic changes, resistance to apoptosis and tumor angiogenesis. In cancer cells, PTGS2 is a key step in the production of prostaglandin E2 (PGE2), which plays important roles in modulating motility, proliferation and resistance to apoptosis.
      Gene NamePTGS2
      GenBank GeneL15326
      GenBank Protein291988
      References
      1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
      2. Lee YS, Kim H, Brahim JS, Rowan J, Lee G, Dionne RA: Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain. 2007 Jun;129(3):279-86. Epub 2006 Dec 18. Pubmed
      3. Hinz B, Cheremina O, Brune K: Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J. 2007 Sep 20;. Pubmed
      4. Weinheimer EM, Jemiolo B, Carroll CC, Harber MP, Haus JM, Burd NA, LeMoine JK, Trappe SW, Trappe TA: Resistance exercise and cyclooxygenase (COX) expression in human skeletal muscle: implications for COX-inhibiting drugs and protein synthesis. Am J Physiol Regul Integr Comp Physiol. 2007 Jun;292(6):R2241-8. Epub 2007 Feb 22. Pubmed
      DrugBank Interactions: 2 of 23
      TargetProstaglandin G/H synthase 1
      Actioninhibitor
      General FunctionProstaglandin-endoperoxide synthase activity
      Specific FunctionConverts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells.
      Gene NamePTGS1
      GenBank GeneM31822
      GenBank Protein387018
      ReferencesChen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
      DrugBank Interactions: 3 of 23
      TargetProstaglandin G/H synthase 3
      ReferencesBotting R, Ayoub SS: COX-3 and the mechanism of action of paracetamol/acetaminophen. Prostaglandins Leukot Essent Fatty Acids. 2005 Feb;72(2):85-7. Pubmed
      View All 23 DrugBank Interactions

  16. Biological Test Results

    1. BioAssay Results

  17. Classification

    1. Ontologies

      1. MeSH Tree

      2. ChEBI Ontology

      3. KEGG: Carcinogen

      4. KEGG: Drug

      5. KEGG: ATC

      6. KEGG: CYP

      7. KEGG: JP15

      8. KEGG: Risk Category of Japanese OTC Drugs

      9. KEGG: OTC drugs

      10. KEGG: Animal Drugs

      11. WHO ATC Classification System

      12. WIPO IPC

  18. Information Sources

    1. HSDB
      ACETAMINOPHEN
      http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+103-90-2
    2. DrugBank
      Acetaminophen
      http://www.drugbank.ca/drugs/DB00316
      http://www.drugbank.ca/drugs/DB00316#targets
      http://www.drugbank.ca/drugs/DB00316#enzymes
      http://www.drugbank.ca/drugs/DB00316#transporters
    3. ILO-ICSC
      PARACETAMOL
      http://www.ilo.org/dyn/icsc/showcard.display?p_card_id=1330
    4. CAMEO Chemicals
      4-hydroxyacetanilide
      https://cameochemicals.noaa.gov/chemical/20492
    5. Human Metabolome Database
      Acetaminophen
      http://www.hmdb.ca/metabolites/HMDB01859
    6. Burnham Center for Chemical Genomics
      SID56422763
      https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table
    7. NCIt
      Acetaminophen
      http://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C198
    8. LiverTox
      Acetaminophen
      https://livertox.nlm.nih.gov//Acetaminophen.htm
    9. EPA Chemicals under the TSCA
      Acetamide, N-(4-hydroxyphenyl)-
      http://www.epa.gov/chemical-data-reporting
    10. European Chemicals Agency - ECHA
      Paracetamol
      https://echa.europa.eu/
      paracetamol
      https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/82701
    11. ChemIDplus
      Acetaminophen [USP:JAN]
      https://chem.nlm.nih.gov/chemidplus/sid/0000103902
    12. NITE-CMC
      4'-Hydroxyacetanilide
      http://www.safe.nite.go.jp/english/ghs/08-meti-0051e.html
    13. The Cambridge Structural Database
      The Cambridge Structural Database provides access to 3D structures of molecules determined experimentally using diffraction techniques.
      http://www.ccdc.cam.ac.uk/pages/Home.aspx
    14. NIST
      Acetaminophen
      http://www.nist.gov/srd/nist1a.cfm
    15. FDA Orange Book
      Patent:9468636
      http://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm
    16. PubMed Health
      Ofirmev
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0000015/
      Ofirmev
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008786/
      Acetaminophen (By mouth)
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008785/
      Acetaminophen (Into the rectum) (Acephen)
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008789/
      Norco
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0010590/
      Percocet
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0011543/
      Tencon
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0009375/
      Pyregesic-C
      http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0008790/
    17. WHO ATC
      http://www.whocc.no/atc/
      ATC Code
      http://www.whocc.no/atc_ddd_index/
    18. OSHA Chemical Sampling Information
      Tylenol
      https://www.osha.gov/dts/chemicalsampling/data/CH_274720.html
    19. DailyMed
      ACETAMINOPHEN
      http://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=ACETAMINOPHEN
    20. FDA/SPL Indexing Data
      362O9ITL9D
      http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/
    21. EPA Office of Pesticide Programs
      The EPA OPP Pesticide Ecotoxicity Database, updated by the Ecological Fate and Effects Division of the EPA Office of Pesticide Programs, contains all EPA reviewed ecotoxicity endpoints for pesticides registered or previously registered in the U.S. Toxicity data. Read more.
      http://www.ipmcenters.org/Ecotox/index.cfm
    22. ClinicalTrials.gov
      arthritis pain|apap|paracetamol|fortolin|counteract pain|p-acetamidophenol|pediacare infant fever pain reliever|datril|mapap|infants tylenol|anacin-3|pharbetol|ofirmev|n-acetyl-p-aminophenol|tylenol extra strength|panadol|acephen|acamol|acetaco|algotropyl|tylenol|dolofin infantil|ringl|acetaminophen|rx act pain relief|xl-dol|neopap|actamin|tempra|nortemp|bf-paradac|childrens pain reliever|stopain|arthritis pain reliever|infants pain reliever|theraflu|up and up acetaminophen|norco|anexsia|percocet|lortab|vicodin es|vicodin hp|norcet|tylox|bancap hc|co-gesic|roxilox|vicodin|lorcet-hd|allay|hy-phen|childrens nortemp|childrens mapap|childrens acetaminophen|childrens mapap acetaminophen|childrens silapap|childrens tylenol|feverall children|acetaminophen extended release|feverall adults|pain and fever|pain reliever rapid release|acetaminophen oral solution|infants acetaminophen|infants silapap|feverall infants|infants mapap|mapap arthritis pain|infants' feverall|childrens pain relief|aspirin free|little fevers childrens fever pain reliever|acetaminophen - apap arthritis|8 hour pain relief|infants pain relief|cetafen extra|ed apap|up and up childrens acetaminophen|preferred plus arthritis pain|childrens pain and fever|extra strength pain reliever|care one pain relief|acetaminophen rapid release|capital|extra strength mapap|acetaminophen extra strength|extra strength acetaminophen|mapap extra strength|7 select acetaminophen|childrens non aspirin|bactimicina childrens pain and fever|childrens pain and fever acetaminophen|leader pain reliever|up and up infants acetaminophen|doliprane|leader arthritis pain|regular strength pain reliever|dafalgan|non-aspirin|arthritis pain relief|pediacare infants fever reducer grape|pediacare childrens fever reducer pain reliever grape|powerful pain medicine|good sense pain relief|junior strength pain reliever|arfen|acetaminophen (red)|infants pain and fever|wygesic|darvocet|rexall pain relief|pediacare infants fever reducer cherry|pediacare childrens fever reducer pain reliever cherry|childrens pain relief acetaminophen|excedrin
      https://clinicaltrials.gov/search?intr=arthritis pain+OR+apap+OR+paracetamol+OR+fortolin+OR+counteract pain+OR+p-acetamidophenol+OR+pediacare infant fever pain reliever+OR+datril+OR+mapap+OR+infants tylenol+OR+anacin-3+OR+pharbetol+OR+ofirmev+OR+n-acetyl-p-aminophenol+OR+tylenol extra strength+OR+panadol+OR+acephen+OR+acamol+OR+acetaco+OR+algotropyl+OR+tylenol+OR+dolofin infantil+OR+ringl+OR+acetaminophen+OR+rx act pain relief+OR+xl-dol+OR+neopap+OR+actamin+OR+tempra+OR+nortemp+OR+bf-paradac+OR+childrens pain reliever+OR+stopain+OR+arthritis pain reliever+OR+infants pain reliever+OR+theraflu+OR+up and up acetaminophen+OR+norco+OR+anexsia+OR+percocet+OR+lortab+OR+vicodin es+OR+vicodin hp+OR+norcet+OR+tylox+OR+bancap hc+OR+co-gesic+OR+roxilox+OR+vicodin+OR+lorcet-hd+OR+allay+OR+hy-phen+OR+childrens nortemp+OR+childrens mapap+OR+childrens acetaminophen+OR+childrens mapap acetaminophen+OR+childrens silapap+OR+childrens tylenol+OR+feverall children+OR+acetaminophen extended release+OR+feverall adults+OR+pain and fever+OR+pain reliever rapid release+OR+acetaminophen oral solution+OR+infants acetaminophen+OR+infants silapap+OR+feverall infants+OR+infants mapap+OR+mapap arthritis pain+OR+infants' feverall+OR+childrens pain relief+OR+aspirin free+OR+little fevers childrens fever pain reliever+OR+acetaminophen - apap arthritis+OR+8 hour pain relief+OR+infants pain relief+OR+cetafen extra+OR+ed apap+OR+up and up childrens acetaminophen+OR+preferred plus arthritis pain+OR+childrens pain and fever+OR+extra strength pain reliever+OR+care one pain relief+OR+acetaminophen rapid release+OR+capital+OR+extra strength mapap+OR+acetaminophen extra strength+OR+extra strength acetaminophen+OR+mapap extra strength+OR+7 select acetaminophen+OR+childrens non aspirin+OR+bactimicina childrens pain and fever+OR+childrens pain and fever acetaminophen+OR+leader pain reliever+OR+up and up infants acetaminophen+OR+doliprane+OR+leader arthritis pain+OR+regular strength pain reliever+OR+dafalgan+OR+non-aspirin+OR+arthritis pain relief+OR+pediacare infants fever reducer grape+OR+pediacare childrens fever reducer pain reliever grape+OR+powerful pain medicine+OR+good sense pain relief+OR+junior strength pain reliever+OR+arfen+OR+acetaminophen (red)+OR+infants pain and fever+OR+wygesic+OR+darvocet+OR+rexall pain relief+OR+pediacare infants fever reducer cherry+OR+pediacare childrens fever reducer pain reliever cherry+OR+childrens pain relief acetaminophen+OR+excedrin
    23. PubChem
      Data deposited in or computed by PubChem
      https://pubchem.ncbi.nlm.nih.gov
    24. MeSH
      Acetaminophen
      https://www.ncbi.nlm.nih.gov/mesh/68000082
      MeSH Tree
      http://www.nlm.nih.gov/mesh/meshhome.html
      Antipyretics
      https://www.ncbi.nlm.nih.gov/mesh/68058633
      Analgesics, Non-Narcotic
      https://www.ncbi.nlm.nih.gov/mesh/68018712
    25. ChEBI
      ChEBI Ontology
      http://www.ebi.ac.uk/chebi/userManualForward.do#ChEBI%20Ontology
    26. KEGG
      Carcinogen
      http://www.genome.jp/dbget-bin/www_bget?brite:br08008
      Drug
      http://www.genome.jp/dbget-bin/www_bget?brite:br08301
      ATC
      http://www.genome.jp/dbget-bin/www_bget?brite:br08303
      JP17
      http://www.genome.jp/dbget-bin/www_bget?brite:br08311
      Risk category of Japanese OTC drugs
      http://www.genome.jp/dbget-bin/www_bget?brite:br08312
      OTC drugs
      http://www.genome.jp/dbget-bin/www_bget?brite:br08313
      Animal drugs
      http://www.genome.jp/dbget-bin/www_bget?brite:br08331
      CYP
      http://www.genome.jp/dbget-bin/www_bget?brite:br08309
    27. WIPO
      International Patent Classification
      http://www.wipo.int/classifications/ipc/
    28. NCBI
      LinkOut is a service that allows one to link directly from NCBI databases to a wide range of information and services beyond NCBI systems.
      https://www.ncbi.nlm.nih.gov/projects/linkout